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Podocyte Injury in Diabetic Nephropathy

Hou-Yong Dai, Yi-De Zhang, Li Fang, Ya-Ping Fan

Hou-Yong Dai, Yi-De Zhang, Li Fang, Ya-Ping Fan, Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, China

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Corresponding Author: FAN Ya-Ping, Professor, Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, China, 226001.
Email: fanyp19107@medmail.com.cn
Telephone: +86-513-8116 0216
Fax: +86-513-85052222

Received: December 8, 2016
Revised: January 22, 2017
Accepted: January 24, 2017
Published online: March 24, 2017

ABSTRACT

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease throughout the world. It is well recognized that podocyte injury plays a critical role in the development and progression of DN. There are many breakthrough in the study of podocyte injury, such as podocyte apoptosis, epithelial-mesenchymal transition (EMT), autophagy and so on, In this review, we discuss pathogenesis of DN, highlight the cause of podocyte injury in DN, which would provide new insight into the prevention and treatment of DN.

Key words: Diabetic nephropathy; Podocyte injury; Apoptosis; Epithelial-mesenchymal transition; Autophage

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Dai HY, Zhang YD, Fang L, Fan YP. Podocyte Injury in Diabetic Nephropathy. Journal of Nephrology Research 2017; 3(1): 122-129 Available from: URL: http://www.ghrnet.org/index.php/jnr/article/view/1922

INTRODUCTION

Diabetic nephropathy (DN) is one of the most common chronic serious complications of diabetes mellitus (DM) and the leading cause of end-stage renal disease. The global prevalence of DM has been increasing, and it is estimated that the people with DM worldwide will increase from 382 million in 2013 to 592 million by 2035, according to the International Diabetes Federation[1]. Moreover, about 15%-25% of type 1 DM and 30%-40% of type 2 DM patients suffer DN[2]. In this regard, it is extremely significant to study the pathogenesis and progressive mechanism of DN and try to delay its progression. However, the pathogenesis of DN remains fully elucidated. At present, many studies show that the development of DN is the results of interaction among genetics; hemodynamics, as well as metabolic factors. Furthermore, recent researches have showed podocyte also plays a critical role in DN progression. In this review, we summarize the present recognitions on the pathogenesis of DN, and highlight the relationship between podocyte injury and DN, which may help us to prevent and treat DN.

PATHOGENESIS of DN RAAS and DN

Renin-angiotensin-aldosterone system (RAAS) was uncovered more than 100 years ago; traditional RAAS includes rennin, angiotensin, aldosterone and related receptors, which maintains the hemodynamic stability and metabolic homeostasis of water and electrolytes, as well as blood pressure. RAAS is divided into systemic and local action according to action targets, and the kidney has complete RAAS system components. RAAS over-activation (especially in kidney) plays an important role in DN, in which Ang Ⅱ is more critical, and elevation of Ang Ⅱ in DN leads to hemodynamics disorder, especially renal hyperfiltration, hypertension and hypertransfusion in glomeruli. Ang Ⅱ can promote proteinuria, meanwhile, TGF-β induced by Ang Ⅱ can damage podocytes, and exacerbate proteinuria[3,4]. In recent years, angiotensin converting enzyme 2 (ACE2) is recognized as an important part of RAAS, and is more highlighted in the pathogenesis of DN. The researches showed that ACE2 expresses in podocyte and mesangial cells, but not in glomerular endothelial cells. ACE2 can physiologically protect the kidney by transforming Ang II to Ang-(1-7) and Ang I to Ang-(1-9)[5]. Both animal experiments[5,6] and human researches[7,8] showed that ACE2 expression was decreased in kidney of DN, and Ang II degeneration decreased, thereafter, accumulated Ang II in kidney jeopardized podocyte and induced proteinuria by means of hemodynamic and non-hemodynamic mechanism[9]. ACE2 inhibitor or knock-out of ACE2 exacerbated the progression of DN, which further indicated that ACE2 decrease played an important role in the development of DN[5,10-12]. Wang et al[13] found that ACE2 excreted in urine was positively related to proteinuria, in this regard, ACE2 has the potential to become a latent biomarker for DN. The role of RAAS on DN was gradually unveiled with the development of recognition to RAAS. In 2002, prorenin receptor (PRR) was first discovered and found it expressed in kidney and other organs. In kidney, PRR expressed on both mesangial cells and podocytes, and could work by biding with prorenin and renin. The binding ability to prorenin of PRR is 2-3 fold higher than its bide to renin[14].

Research showed that prorenin binds to PRR to transform into renin with catalytic activity by means of change of molecular conformation and exposure to active site, then Ang II generates and participates in the pathogenesis of DN (Ang II dependent pathway). On the other hand, prorenin binding to PRR can directly activate intracellular MAPK (Ang II independent pathway), thereafter increase mesangial TGF-β level and matrix protein acumulation[14]. Experiments found that PRR expression increase in both type 1[15,16] and type 2[17] DN animal models, and PRR blockers can inhibit its activity, and postpone DN progression, which indicate PRR play an significant role on the development of DN[18]. Recent study found that PRR induced increases of inflammatory factor TNF-a and IL-1β expression, which participate in the development of DN. PRR blockers can decrease both TNF-a and IL-1β expression, and reduce proteinuria as well[19]. PRR is expected to become a new target for the treatment of DN by intensive study its role on the pathogenesis of DN.

OXIDATIVE STRESS and DN

Other than hemodynamic factor, metabolic disorders also play a critical role on pathogenesis of DN. Prolonged exposure to hyperglycemia is an initiating factor for DN. In the later stages of diabetes, even if blood glucose control is satisfactory, a series of subsequent reactions caused by hyperglycemia still lead to DN progression because of so-called “glucose memory”. The ADVANCE study indicated the role of hyperglycemia on pathogenesis in DN, and intensive blood glucose control reduced the risk of at least 10% to endpoint events, and relative risk of 21% to DN[20]. Intracellular glucose dysmetabolism under the situation of hyperglycemia activated a series of signal pathways; generated ROS products, TGF-β, advanced glycosylation end products (AGEs), as well as MCP-1, eventually lead to a series of diabetic complications. Glycosamine intermediate product transformed from fructose-6 -phosphate can further generate ROS and TGF-β after hexosamine pathway activation. DAG-PKC signal pathway can also generate inflammatory factors, such as ROS and TGF-β. In setting of DM, AGEs accumulate in the body, and when AGEs bind to AGE receptors, increased ROS will lead to oxidative stress and inflammation factors release, all of these changes will eventually lead to renal injury. Meanwhile, hyperglycemia activate polyol metabolic pathway and consume a lot of reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH). NADPH is important to maintain the normal level of glutathione (GSH) that plays a vital role in ROS clearance in cells, in this regard, reduction of NADPH give rise to oxidative stress by means of GSH reduction and ROS accumulation.

Giacco et al[21] comprehensively analyzed the roles of various metabolic factors on complications of DM and found that oxidative stress is the common pathway for DN. Normally, production and clearance of ROS are in balance, however, ROS increase or antioxidant decrease induced by various factors in DM setting can contribute to oxidative stress[22,23]. Oxidative stress play a critical role in the pathogenesis of DN, increased ROS can inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by activating poly ADP-ribose polymerase (PARP), then cause glycolysis dysfunction, eventually lead to complications of DM due to various metabolic pathway activation[21,24].

Recent research showed that RAAS activation and oxidative stress were not isolated in the pathogenesis of DN, they cross-talk each other and together contribute to progression of DN[25,26]. Both ACEI and ARB can protect the kidney by not only lowering blood pressure, but also inhibiting AGEs production, which confirms the cross-talk between hemodynamics and metabolic factors[27,28]. ROS in body mainly derives from NADPH oxidase[29], in the states of disease, metabolic disorder produce excessive ROS, moreover, in early stage of DM, AngⅡ also results in the generation of excessive ROS by inducing NADPH oxidase[30].

ROLE of PODOCYTE in DN

Glomerular filtration barrier (GFB) includes charge barrier and size barrier. There are 3 layers, including endothelial cell, glomerular basement membrane and podocyte, the latter is the critical part of GFB. Podycyte derives from mesenchyme cell during fetal development, and loses its proliferative ability after maturity. Podocyte is consisted of cell body, primary processes and foot processes. Combined with endothelia cell and glomerular basement membrane (GBM), podocytes maintain normal glomerular filtration function by attaching on GBM with foot processes, and the injury of podocyte structure and function would lead to proteinuria. Various studies showed podocytopathy is a cardinal issue for pathogenesis of DN[31-35], and podocyte injuries include cellular hypertrophy, foot processes effacement, and podocyte detachment. Decreased number of podocyte gives rise to glomerular capillary loop collapse, GBM exposure, adhesion to Bowman’s capture; finally result in glomerulosclerosis[36].

PODOCYTE HYPERTROPHY

Cell hypertrophy is a common kind of pathological alteration in the body, and it means the cell cycle is stagnated in set point of G1/S phase, fail to synthesize DNA with the increase of protein synthesis. That is a common adaptive pathological process, under this condition, the cell volume increases, but the number is unchanged[37]. In the setting of DM, hyperglycemia and mechanical stress acting on podocyte, leading to increase podocyte volume and inhibit podocyte proliferation by enhancing the expression of cyclin dependent kinase inhibitor P27Kip[38, 39]. Xu et al[40] found that AngⅡ involved in podocyte enlargement process, and angiotensinⅡ receptor blocker (ARB) could inhibit p27Kip1 expression. AGEs also play an important role in podocyte injury in the early stage of DN[41]. Hyperfiltration, hypertension and hyperperfusion in glomeruli in DM situation lead to glomerular hypertrophy, podocyte adaptive hypertrophy as well in order to maintain normal glomerular structure and function. However, podocyte density decrease to a certain extent will give rise to podocyte detachment[42]. Recently, Herbach et al[43] found that podocyte hypertrophy was earlier than glomeruli enlargement in the development of DN, indicating that podocyte hypertrophy is critical for DN.

PODOCYTE LOSSES

In addition to podocyte hypertrophy in DN, attention to podocyte loss was also paid by many studies in earlier time. Podocyte loss was very common in both type 1 and type 2 DN patients, and there was positive correlation between podocyte loss and proteinuria progression[44-47]. Previous studies showed that podocyte density in glomeruli was more valuable than podocyte loss to predict progression of DN[48,49]. The other reasons for podocyte loss include apoptosis, detachment, as well as decrease of podocyte regeneration.

Podocyte apoptosis

Podocyte apoptosis was verified as an important contributing reason to pathogenesis of DN in most experiments. Susztak found ROS in the setting of hyperglycemia could activate both p38MAPK and caspase-3 not only in vitro, but in vivo of animal model, eventually cause proteinuria[50]. AGEs can also activate FOXO4 transcription factor through p38MAPK signal pathway, then lead to podocyte apoptosis[51]. Increased ROS due to up-regulation of 20-HETE and NADPH oxidase by cytochrome in hyperglycemia situation can also cause podocyte apoptosis[52]. Recently, it has been found that Notch1 signal dependent activation of p53, rather than p38MAPK, was involved in the occurrence of podocyte apoptosis, which is considered as a new way of podocyte apoptosis[53]. Further study indeciated that Notch expression of podocyte correlated with proteinuria and glomerular sclerosis, so Notch activations may be the general pathogenesis of acquired kidney diseases, including DN[54].

Normally, proapoptotic and anti-apoptotic signal pathways exist simultaneously in body and keep dynamic equilibrium, and maintain stability of internal environment. Decreased activity of anti-apoptotic signal is a critical reason for podocyte apoptosis. PI3K/AKT pathway in podocyte can inhibit podocyte apoptosis, experiments showed that AKT phosphorylation reduction could cause increase of podocyte apoptosis of db/db mice[55]. Various reasons such as hyperglycemia, AGEs, oxidative stress, AngⅡ, as well as TGF-β act on podocyte concomitantly in DN, then lead to podocyte loss by activating apoptotic pathway and down-regulating anti-apoptosis signal pathway.

Podocyte detachment

A research on urinalysis of 50 patients with type 2 diabetes showed that urinary podocytes were detected in 53% patients with microalbuminuria and 80% with macroalbuminuria, whereas absent in healthy controls, diabetic patients with normoalbuminuria and diabetic patients with chronic renal failure[56]. Further, some living but not apoptotic podocytes were found in the urine of animal models and patients with DN, demonstrating that podocyte detachment is another reason for podocyte loss[57,58]. Some researchers considered that podocyte in urine occurred earlier than proteinuria to reflect kidney injury, in this regard; podocyte in urine was a biomarker in early stage of DN[56,59].

Podocyte structure and function is maintained by attaching GBM through α3β1 integrin and deglycosylation, cytoskeleton rearrangement, decrease of surface negative charge and integrin expression give rise to podocyte detachment[37]. It is showed that decrease of α3β1 integrin expression between podocyte and GBM in hyperglycemia is an important reason for podocyte detachment[60]. In addition, mechanical stress and TGF-β reduce podocyte adhesion ability by down-regulating α3β1 integrin expression[61]. Chen et al found that α3β1 integrin expression and podocyte adhesion ability decreased in podocyte cultured with high glucose milieu, and integrin linked kinase (ILK) expression increased; however, astragalin IV can inhibit ILK expression and up-regulate α3β1 integrin, and improve podocyte adhesion ability[62]. Han et al found that podocyte phenotype altered and its adhesion capability decreased with both ILK and β1 integrin expression up-regulation under the stimulation of either high glucose solute or AngⅡ, which are improved by ARB treatment[63]. The reason why podocyte detachment with different integrin level still remains to be elucidated.

Epithelial-mesenchymal transition (EMT)

EMT is another pathogenesis for podocyte loss in DN. During the process of EMT, podocytes loss some normal epithelial markers but acquire mesenchymal markers. Li et al found that TGF-β could induce podocyte phenotype change by downregulating the expression of epithelial biomarkers such as nephrin, ZO-1, P-cadherin, whereas upregulating the expression of mesenchymal markers such as desmin, FSP-1 (fibroblast-specific protein-1), MMP-9 (matrix metalloproteinase-9) and fibronectin[64]. Recently, some questions have been raised about the origin of the detachment of podocytes in urine, which is derived from visceral epithelial cells or parietal epithelial cells[65]. Yamaguchi et al found that, in urinary sediment, about 86% of podocyte expressed FSP-1, in which 95% were without apoptosis[66]. FSP-1 was also found in kidney tissue specimen, the level of FSP-1 correlated with proteinuria, podocyte loss, as well as severity of kidney pathology, these findings firmly verified that EMT is one of the reasons for podocyte loss. Our previous studies in vivo[67] and in vitro[68,69] have also demonstrated that podocytes undergo EMT in DN. Thus, how to protect podocyte from EMT is an important issue in the field of DN research.

Lack of podocyte proliferation

Cell growth depends on the normal cell cycle; and the latter is tightly regulated by the cell cycle regulatory proteins in the cell nucleus. Positive regulation will promote cell cycle; however, negative regulation will inhibit cell proliferation. Positive regulative proteins of cell cycle include cyclin and cyclin dependent kinase (CDK), both of which have activity after binding together to form complex. Cyclin dependent kinase inhibitor (CDKI) can specifically bind with CDK, and then inhibit cell proliferation. There are 2 types of CDKI, one is INK family including P15, P16, P18 and P19, the other is CIP/KIP family including P21, P27 and P57, the latter is most studied[37].

In response to various injury stresses, the lack of proliferation is one of the reasons which lead to the loss of podocyte[37]. Podocyte is a kind of terminally differentiated cell. In normal resting state, podocyte expresses P27 and P57, but not P21[70]. It is reported that podocyte is lack of proliferation in membranous nephropathy (MN), DN and typical focal segmental glomerulosclerosis (FSGS), whereas it is capable of proliferating in HIV associated nephropathy, cresentic nephritis and cellular proliferating FSGS. The reason why different patterns of podocyte mentioned above is experimentally studied due to abnormal expressions of P27, P57 and P21. In the setting of DN, podocyte stimulated by high glucose overexpresses p27Kip1, which can inhibit podocyte proliferation, and attenuation of p21Kip1 gene would ameliorate podocyte injury in DN[71,72].

Another important kinase that plays a key role in the regulation of podocyte biology is Cdk5, which is activated and regulated by p35 and cyclin I and has been shown to control podocyte survival. The Cdk5 probably stabilizes the prosurvival protein Bcl­2 and protects podocytes against apoptosis in vitro and in vivo[73,74].

Podocyte autophagy

Autophagy is regarded as a major catabolic process in a cell that degrades and recycles macromolecules and damaged organelles to maintain intracellular homeostasis and cell integrity[75]. In the kidney, emerging evidence shows that autophagy plays a critical role in the maintenance of kidney homeostasis and disease pathogenesis[76,77]. In normal condition, our previous study and others indicated that podocytes have a high level of basal autophagy, which are important for their maintenance of cellular homeostasis. Importantly, impaired podocyte autophagy exacerbates proteinuria in DN[75-77]. Several studies have shown that hyperactivation of the mTOR pathway plays a pivotal role and is associated with podocyte injury in DN. It is reported that mTOR plays a major role in the negative regulation of autophagy. In contrast, AMPK is a positive regulator of autophagy, furthermore, it can crosstalk with the mTORC1 signal during multiple steps of autophagy regulation. Sirt1, one of the members of sirtuins, has been shown to induce autophagy and may contribute to a renoprotective effects in DN. Thus, activation of autophagy may be a therapeutic option for the prevention and treatment of DN[78,79]. Our study indicated that treatment with the mTORC1 inhibitor rapamycin restored autophagic activity and attenuated hyperglycemia-induced podocyte injury[80]. Furthermore, autophagy inhibition induced podocyte apoptosis, which provide a new insight into the interaction between autophagy and apoptosis in the injury of podocyte. There was a report that autophagy inhibition induced podocyte apoptosis by activating the pro-apoptotic pathway of endoplasmic reticulum stress[81].

PODOCYTE RELATED PROTEINS

It is demonstrated that podocyte is composed of three parts according to its celluar structure: the apical membrane domain, the junctional domain, and the basal domain[82]. The apical membrane domain consists of podocalyxin, podoplanin and podoendin, which carry negative charges and acts as a charge barrier to prevents albumin filtered from glomeruli. The junctional domain including nephrin, podocin, ZO-1 and CD2AP, which were important parts of slit diaphragm (SD) and acts as mechanical barrier. The basal domain mainly consists of α3β1 integrin and dystroglycans, which are mainly in charge of adhesion between podocyte and GBM to prevent podoctye detachment.

SD is a key structure of selective filtration barrier of kidney, acts as a bridge between foot processes. SD consists of a series of protein complexes in the extracellular space of podocytes. Interaction of these protein complexes can not only maintain normal podocyte structure and biological function, but also intimately relate to proteinuria. Nephrin is an important part of SD, also well studied. Nephrin was discovered in 1999 by Tryggvason, it is one of immunoglobulin super family and coded by NPHS1 gene with molecular weight 180kd. Nephrin is a transmembrane protein with cytoplasmic domain and plasmalemma domain[82]. Substantial evidence indicates that nephrin-CD2AP-podocin complex is a key functional unit to rivet SD on cytoskeleton of podocyte cytotactin so as to maintain normal glomerular filtration function[83-87]. One of cross-sectional studies on DM showed that 17% of microalbuminuria patients and 28% of heavy proteinuria patients were detected nephrin in urine, but there was no nephrin in normal control group[88]. Meanwhile, nephrin expression decreases in both types 1 and type 2 DN, and correlate with progression of renal diseases[89-93]. Both ACEI and ARB can prevent nephrin reduction, however, calcium channel blocker and endothelin receptor antagonist can not, which indicate that AngⅡis one of the pathogenesis in nephrin reduction[94-97].

Coward et al [98] found that podocyte was a kind of insulin sensitive cells, and was the insulin target. Nephrin plays an important role on uptaking of insulin and glocuse metabolite in podocyte under the setting of high glucose [99]. Compared with normal nephrin expression cells, podocyte without nephrine expression had no response to insulin, and its capability of uptaking glucose induced by insulin apparently reduced, however, podocyte without nephrin expression transfected with nephrin gene could revert glucose uptake capability induced by insulin[99]. Further study showed that podocyte insulin specific signal defect participated in early stage of occurrence and development of DN[99].

In addition to nephrin, expression of both P-cadherin and ZO-1 decreased prominently in DN[100,101]. Not all podocyte related proteins reduce; CD2AP and podocin are intact in DN[90,91]. Further studies needed to elucidate the interrelationship between nephrin and other SD related proteins.

TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL 6 (TRPC6) and PODOCYTE

Podocytes injury is considered a major contributor to the development and progression of DN. In normal conditions, the physiological function of podocytes is dependent on their handling capacity of intracellular calcium. Excessive calcium influx in podocytes may result in the effacement of foot processes, apoptosis, and subsequent glomeruli damage. One of the main proteins responsible for calcium flux in podocytes is TRPC6, which is a channel in glomerular slit diaphragm [102]. Compelling data have indicated that this channel play a critical role in various kidney diseases, including DN[103-105]. A lot of efforts have been done to unraveling the pathogenesis of TRPC6-mediated podocyte injury in DN. It is indicated that TRPC6 is located on the podocyte membrane, where it is integrated into a signaling complex that interacts with nephrin and other podocyte related proteins[102,106,107]. Ilatovskaya et al found that angiotensin II-dependent activation of TRPC6 is implicated in type 1 DN[105]. Liu et al found that high glucose induced apoptosis in podocytes which express TRPC6, but not in TRPC6 knockdown podocytes, furthermore, the cause of apoptosis was due to the elevation of ROS by stimulating TRPC6 in high glucose condition[108]. Another study demonstrated that high glucose modified TRPC6 channels via increased oxidative stress and syndecan-4 in human podocytes[109].

CONCLUSION

Up to now, metabolic disorders, hemodynamic abnormalities and different gene background are implicated in the pathogenesis of DN. Most of these factors firstly cause podocyte injury, destroy filtration barrier, and then give rise to proteinuria, the latter lead to tubular-interstitial inflammation, eventually kidney fibrosis. According to the pathogenesis of DN, it is beneficial to prevent DN clinically by correcting metabolic and hemodynamic disorder, especially protect the podocyte as early as possibe.

REFERENCES

1. Shi Y, Hu FB. The global implications of diabetes and cancer. Lancet 2014; 383: 1947-1948. [DOI: 10.1016/S0140-6736(14)60886-2]

2. Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev 2004; 25: 971-1010. [DOI: 10.1210/er.2003-0018]

3. Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: where hemodynamics meets metabolism. Exp Clin Endocrinol Diabetes 2007; 115: 69-84. [DOI: 10.1055/s-2007-949721]

4. Giunti S, Barit D, Cooper ME. Mechanisms of diabetic nephropathy: role of hypertension. Hypertension 2006; 48: 519-526. [DOI: 10.1161/01.HYP.0000240331.32352.0c]

5. Leehey DJ, Singh AK, Bast JP, Sethupathi P, Singh R. Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. Transl Res 2008; 151: 208-216. [DOI: 10.1016/j.trsl.2008.01.003]

6. Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D.Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol 2006; 17: 3067-3075. [DOI: 10.1681/ASN.2006050423]

7. Mizuiri S, Hemmi H, Arita M, Ohashi Y, Tanaka Y, Miyagi M, Sakai K, Ishikawa Y, Shibuya K, Hase H, Aikawa A.Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis 2008; 51: 613-623. [DOI: 10.1053/j.ajkd.2007.11.022]

8. Reich HN, Oudit GY, Penninger JM, Scholey JW, Herzenberg AM.Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int 2008; 74: 1610-1616. [DOI: 10.1038/ki.2008.497]

9. Batlle D, Soler MJ, Wysocki J. New aspects of the renin-angiotensin system: angiotensin-converting enzyme 2 - a potential target for treatment of hypertension and diabetic nephropathy. Curr Opin Nephrol Hypertens 2008; 17: 250-257. [DOI: 10.1097/MNH.0b013e3282f945c2]

10. Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D.ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int 2007; 72: 614-623. [DOI: 10.1038/sj.ki.5002373]

11. ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes. Diabetes 2008; 57: 1018-1025. [DOI: 10.2337/db07-1212]

12. Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC, Backx PH, Penninger JM, Herzenberg AM, Scholey JW.Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. The American journal of pathology 2007; 171: 438-451. [DOI: 10.2353/ajpath.2007.060977]

13. Urinary mRNA expression of ACE and ACE2 in human type 2 diabetic nephropathy. Diabetologia 2008; 51: 1062-1067. [DOI: 10.1007/s00125-008-0988-x]

14. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417-1427. [DOI: 10.1172/JCI14276]

15. Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, Tada Y, Koura Y, Nishiyama A, Okada H, Uddin MN, Nabi AH, Ishida Y, Inagami T, Saruta T.Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest 2004; 114: 1128-1135. [DOI: 10.1172/JCI21398]

16. Takahashi H, Ichihara A, Kaneshiro Y, Inomata K, Sakoda M, Takemitsu T, Nishiyama A, Itoh H. Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade. J Am Soc Nephrol 2007; 18: 2054-2061. [DOI: 10.1681/ASN.2006080820]

17. Ichihara A, Sakoda M, Kurauchi-Mito A, Nishiyama A, Itoh H.Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. J Am Soc Hypertens 2008; 2: 332-340. [DOI: 10.1016/j.jash.2008.04.009]

18. Ichihara A, Sakoda M, Mito-Kurauchi A, Itoh H. Activated prorenin as a therapeutic target for diabetic nephropathy. Diabetes Res Clin Pract 2008; 82 Suppl 1: S63-66. [DOI: 10.1016/j.diabres.2008.09.027]

19. Matavelli LC, Huang J, Siragy HM. (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin Exp Pharmacol Physiol 2010; 37: 277-282. [DOI: 10.1111/j.1440-1681.2009.05292.x]

20. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P,Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572. [DOI: 10.1056/NEJMoa0802987]

21. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107: 1058-1070. [DOI: 10.1161/CIRCRESAHA.110.223545]

22. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813-820. [DOI: 10.1038/414813a]

23. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-790. [DOI: 10.1038/35008121]

24. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54: 1615-1625. [PMID: 15919781]

25. Yamagishi S, Fukami K, Ueda S, Okuda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 2007; 8: 952-959. [PMID: 17691932]

26. Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid Med Cell Longev 2010; 3: 101-108. [DOI: 10.4161/oxim.3.2.11148]

27. Thomas MC, Tikellis C, Burns WM, Bialkowski K, Cao Z, Coughlan MT, Jandeleit-Dahm K, Cooper ME, Forbes JM. Interactions between renin angiotensin system and advanced glycation in the kidney. J Am Soc Nephrol 2005; 16: 2976-2984. [DOI: 10.1681/ASN.2005010013]

28. Fukami K, Yamagishi S, Ueda S, Okuda S. Novel therapeutic targets for diabetic nephropathy. Endocr Metab Immune Disord Drug Targets 2007; 7: 83-92. [PMID: 17584148]

29. Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM.NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006; 8: 691-728. [DOI: 10.1089/ars.2006.8.691]

30. Li JM, Shah AM. ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy. J Am Soc Nephrol 2003; 14: S221-226. [PMID: 12874435]

31. Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 2005; 54: 1626-1634. [PMID: 1591978]

32. Marshall SM. The podocyte: a potential therapeutic target in diabetic nephropathy? Curr Pharm Des 2007; 13: 2713-2720. [PMID: 17897015]

33. Li JJ, Kwak SJ, Jung DS, Kim JJ, Yoo TH, Ryu DR, Han SH, Choi HY, Lee JE, Moon SJ, Kim DK, Han DS, Kang SW.Podocyte biology in diabetic nephropathy. Kidney Int Suppl 2007: S36-42. [DOI: 10.1038/sj.ki.5002384]

34. Reddy GR, Kotlyarevska K, Ransom RF, Menon RK. The podocyte and diabetes mellitus: is the podocyte the key to the origins of diabetic nephropathy? Curr Opin Nephrol Hypertens 2008; 17: 32-36. [DOI: 10.1097/MNH.0b013e3282f2904d]

35. Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 2008; 4: 39-45. [PMID: 18220694]

36. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 2005; 67: 404-419. [DOI: 10.1111/j.1523-1755.2005.67097.x]

37. Shankland SJ. The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006; 69: 2131-2147. [DOI: 10.1038/sj.ki.5000410]

38. Petermann AT, Pippin J, Durvasula R, Pichler R, Hiromura K, Monkawa T, Couser WG, Shankland SJ. Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int 2005; 67: 157-166. [DOI: 10.1111/j.1523-1755.2005.00066.x]

39. Kim NH. Podocyte hypertrophy in diabetic nephropathy. Nephrology (Carlton) 2005; 10 Suppl: S14-16. [DOI: 10.1111/j.1440-1797.2005.00450.x]

40. Xu ZG, Yoo TH, Ryu DR, Cheon Park H, Ha SK, Han DS, Adler SG, Natarajan R, Kang SW.Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli. Kidney Int 2005; 67: 944-952. [DOI: 10.1111/j.1523-1755.2005.00158.x]

41. Rüster C, Bondeva T, Franke S, Förster M, Wolf G.Advanced glycation end-products induce cell cycle arrest and hypertrophy in podocytes. Nephrol Dial Transplant 2008; 23: 2179-2191. [DOI: 10.1093/ndt/gfn085]

42. Lewko B, Stepinski J. Hyperglycemia and mechanical stress: targeting the renal podocyte. J Cell Physiol 2009; 221: 288-295. [DOI: 10.1002/jcp.21856]

43. Herbach N, Schairer I, Blutke A, Kautz S, Siebert A, Göke B, Wolf E, Wanke R.Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis. American journal of physiology 2009; 296: F819-829. [DOI: 10.1152/ajprenal.90665.2008]

44. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW.Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997; 99: 342-348. [DOI: 10.1172/JCI119163]

45. Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 1999; 42: 1341-1344. [DOI: 10.1007/s001250051447]

46. Steffes MW, Schmidt D, McCrery R, Basgen JM. Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int 2001; 59: 2104-2113. [DOI: 10.1046/j.1523-1755.2001.00725.x]

47. White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, De Cosmo S, Viberti G.Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002; 51: 3083-3089. [PMID: 12351451]

48. Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P.Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 2003; 52: 1031-1035. [PMID: 12663476]

49. Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC 3rd.Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 2006; 7: 6. [DOI: 10.1186/1471-2369-7-6]

50. Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 2006; 55: 225-233. [PMID: 16380497]

51. Chuang PY, Yu Q, Fang W, Uribarri J, He JC.Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor. Kidney Int 2007; 72: 965-976. [DOI: 10.1038/sj.ki.5002456]

52. Eid AA, Gorin Y, Fagg BM, Maalouf R, Barnes JL, Block K, Abboud HE.Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes 2009; 58: 1201-1211. [DOI: 10.2337/db08-1536]

53. Niranjan T, Bielesz B, Gruenwald A, Ponda MP, Kopp JB, Thomas DB, Susztak K.The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 2008; 14: 290-298. [DOI: 10.1038/nm1731]

54. Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T, Si H, Thomas DB, Pullman JM, Melamed ML, Susztak K.Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int 2010; 78: 514-522. [DOI: 10.1038/ki.2010.172]

55. Tejada T, Catanuto P, Ijaz A, Santos JV, Xia X, Sanchez P, Sanabria N, Lenz O, Elliot SJ, Fornoni A.Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int 2008; 73: 1385-1393. [DOI: 10.1038/ki.2008.109]

56. Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I, Koide H.Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant 2000; 15: 1379-1383. [PMID: 10978394]

57. Petermann AT, Pippin J, Krofft R, Blonski M, Griffin S, Durvasula R, Shankland SJ.Viable podocytes detach in experimental diabetic nephropathy: potential mechanism underlying glomerulosclerosis. Nephron Exp Nephrol 2004; 98: e114-123. [DOI: 10.1159/000081555]

58. Vogelmann SU, Nelson WJ, Myers BD, Lemley KV. Urinary excretion of viable podocytes in health and renal disease. American journal of physiology 2003; 285: F40-48. [DOI: 10.1152/ajprenal.00404.2002]

59. Yu D, Petermann A, Kunter U, Rong S, Shankland SJ, Floege J.Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol 2005; 16: 1733-1741. [DOI: 10.1681/ASN.2005020159]

60. Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, Lai YH.Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci 2000; 67: 2345-2353. [PMID: 11065181]

61. Dessapt C, Baradez MO, Hayward A, Dei Cas A, Thomas SM, Viberti G, Gnudi L.Mechanical forces and TGFbeta1 reduce podocyte adhesion through alpha3beta1 integrin downregulation. Nephrol Dial Transplant 2009; 24: 2645-2655. [DOI: 10.1093/ndt/gfp204]

62. Chen J, Gui D, Chen Y, Mou L, Liu Y, Huang J.Astragaloside IV improves high glucose-induced podocyte adhesion dysfunction via alpha3beta1 integrin upregulation and integrin-linked kinase inhibition. Biochem Pharmacol 2008; 76: 796-804. [DOI: 10.1016/j.bcp.2008.06.020]

63. Han SY, Kang YS, Jee YH, Han KH, Cha DR, Kang SW, Han DS.High glucose and angiotensin II increase beta1 integrin and integrin-linked kinase synthesis in cultured mouse podocytes. Cell Tissue Res 2006; 323: 321-332. [DOI: 10.1007/s00441-005-0065-4]

64. Li Y, Kang YS, Dai C, Kiss LP, Wen X, Liu Y.Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. The American journal of pathology 2008; 172: 299-308. [DOI: 10.2353/ajpath.2008.070057]

65. Skoberne A, Konieczny A, Schiffer M. Glomerular epithelial cells in the urine: what has to be done to make them worthwhile? American journal of physiology 2009; 296: F230-241. [DOI: 10.1152/ajprenal.90507.2008]

66. Yamaguchi Y, Iwano M, Suzuki D, Nakatani K, Kimura K, Harada K, Kubo A, Akai Y, Toyoda M, Kanauchi M, Neilson EG, Saito Y.Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis 2009; 54: 653-664. [DOI: 10.1053/j.ajkd.2009.05.009]

67. Dai HY, Zheng M, Tang RN, Ni J, Ma KL, Li Q, Liu BC.Effects of angiotensin receptor blocker on phenotypic alterations of podocytes in early diabetic nephropathy. Am J Med Sci 2011; 341: 207-214. [DOI: 10.1097/MAJ.0b013e3182010da9]

68. Dai HY, Zheng M, Lv LL, Tang RN, Ma KL, Liu D, Wu M, Liu BC.The roles of connective tissue growth factor and integrin-linked kinase in high glucose-induced phenotypic alterations of podocytes. J Cell Biochem 2012; 113: 293-301. [DOI: 10.1002/jcb.23355]

69. Dai H, Zhang Y, Yuan L, Wu J, Ma L, Shi H. CTGF mediates high-glucose induced epithelial-mesenchymal transition through activation of beta-catenin in podocytes. Ren Fail 2016;38:171 1-1716. [DOI: 10.3109/0886022X.2016.1158069]

70. Shankland SJ, Eitner F, Hudkins KL, Goodpaster T, D'Agati V, Alpers CE.Differential expression of cyclin-dependent kinase inhibitors in human glomerular disease: role in podocyte proliferation and maturation. Kidney Int 2000; 58: 674-683. [DOI: 10.1046/j.1523-1755.2000.00213.x]

71. Wolf G, Schanze A, Stahl RA, Shankland SJ, Amann K.p27Kip1 Knockout mice are protected from diabetic nephropathy: evidence for p27Kip1 haplotype insufficiency. Kidney Int 2005; 68: 1583-1589. [DOI: 10.1111/j.1523-1755.2005.00570.x]

72. Fan YP, Weiss RH. Exogenous attenuation of p21Waf1/Cip1 decreases mesangial cell hypertrophy as a result of hyperglycemia and IGF-1. J Am Soc Nephrol. 2004; 15: 575-584. [PMID: 14978159]

73. Brinkkoetter PT, Olivier P, Wu JS, Henderson S, Krofft RD, Pippin JW, Hockenbery D, Roberts JM, Shankland SJ.Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells. J Clin Invest 2009; 119: 3089-3101. [DOI: 10.1172/JCI37978]

74. Brinkkoetter PT, Wu JS, Ohse T, Krofft RD, Schermer B, Benzing T, Pippin JW, Shankland SJ.p35, the non-cyclin activator of Cdk5, protects podocytes against apoptosis in vitro and in vivo. Kidney Int 2010; 77: 690-699. [DOI: 10.1038/ki.2009.548]

75. Crotzer VL, Blum JS. Autophagy and adaptive immunity. Immunology 2010; 131: 9-17. [DOI: 10.1111/j.1365-2567.2010.03321.x]

76. Wang Z, Choi ME. Autophagy in kidney health and disease. Antioxid Redox Signal 2014; 20: 519-537. [DOI: 10.1089/ars.2013.5363]

77. Huber TB, Edelstein CL, Hartleben B, Inoki K, Jiang M, Koya D, Kume S, Lieberthal W, Pallet N, Quiroga A, Ravichandran K, Susztak K, Yoshida S, Dong Z.Emerging role of autophagy in kidney function, diseases and aging. Autophagy 2012; 8: 1009-1031. [DOI: 10.4161/auto.19821]

78. Tanaka Y, Kume S, Kitada M, Kanasaki K, Uzu T, Maegawa H, Koya D.Autophagy as a therapeutic target in diabetic nephropathy. Exp Diabetes Res 2012; 2012: 628978. [DOI: 10.1155/2012/628978]

79. Ding Y, Choi ME. Autophagy in diabetic nephropathy. J Endocrinol 2015; 224: R15-30. [DOI: 10.1530/JOE-14-0437]

80. Fang L, Zhou Y, Cao H, Wen P, Jiang L, He W, Dai C, Yang J.Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS One 2013; 8: e60546. [DOI: 10.1371/journal.pone.0060546]

81. Fang L, Li X, Luo Y, He W, Dai C, Yang J.Autophagy inhibition induces podocyte apoptosis by activating the pro-apoptotic pathway of endoplasmic reticulum stress. Exp Cell Res 2014; 322: 290-301. [DOI: 10.1016/j.yexcr.2014.01.001]

82. Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001; 108: 1583-1587. [DOI: 10.1172/JCI14629]

83. Huber TB, Kottgen M, Schilling B, Walz G, Benzing T.Interaction with podocin facilitates nephrin signaling. J Biol Chem 2001; 276: 41543-41546. [DOI: 10.1074/jbc.C100452200]

84. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attié T, Gubler MC, Antignac C.Podocin localizes in the kidney to the slit diaphragm area. The American journal of pathology 2002; 160: 131-139. [DOI: 10.1016/S0002-9440(10)64357-X]

85. Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P.Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 2001; 108: 1621-1629. [DOI: 10.1172/JCI12849]

86. Shih NY, Li J, Cotran R, Mundel P, Miner JH, Shaw AS.CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. The American journal of pathology 2001; 159: 2303-2308. [DOI: 10.1016/S0002-9440(10)63080-5]

87. Li C, Ruotsalainen V, Tryggvason K, Shaw AS, Miner JH.CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. American journal of physiology 2000; 279: F785-792. [PMID: 10997929]

88. Pätäri A, Forsblom C, Havana M, Taipale H, Groop PH, Holthöfer H.Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes 2003; 52: 2969-2974. [PMID: 14633858]

89. Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, Camussi G.Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 2003; 52: 1023-1030. [PMID: 12663475]

90. Koop K, Eikmans M, Baelde HJ, Kawachi H, De Heer E, Paul LC, Bruijn JA.Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol 2003; 14: 2063-2071. [PMID: 12874460]

91. Benigni A, Gagliardini E, Tomasoni S, Abbate M, Ruggenenti P, Kalluri R, Remuzzi G.Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int 2004; 65: 2193-2200. [DOI: 10.1111/j.1523-1755.2004.00636.x]

92. Langham RG1, Kelly DJ, Cox AJ, Thomson NM, Holthöfer H, Zaoui P, Pinel N, Cordonnier DJ, Gilbert RE.Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. Diabetologia 2002; 45: 1572-1576. [DOI: 10.1007/s00125-002-0946-y]

93. Cooper ME, Mundel P, Boner G. Role of nephrin in renal disease including diabetic nephropathy. Semin Nephrol 2002; 22: 393-398. [PMID: 12224046]

94. Mifsud SA, Allen TJ, Bertram JF, Hulthen UL, Kelly DJ, Cooper ME, Wilkinson-Berka JL, Gilbert RE.Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade. Diabetologia 2001; 44: 878-882. [DOI: 10.1007/s001250100561]

95. Gross ML, El-Shakmak A, Szábó A, Koch A, Kuhlmann A, Münter K, Ritz E, Amann K. ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy. Diabetologia 2003; 46: 856-868. [DOI: 10.1007/s00125-003-1106-8]

96. Kelly DJ, Aaltonen P, Cox AJ, Rumble JR, Langham R, Panagiotopoulos S, Jerums G, Holthöfer H, Gilbert RE.Expression of the slit-diaphragm protein, nephrin, in experimental diabetic nephropathy: differing effects of anti-proteinuric therapies. Nephrol Dial Transplant 2002; 17: 1327-1332. [PMID: 12105259]

97. Bonnet F, Cooper ME, Kawachi H, Allen TJ, Boner G, Cao Z.Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia 2001; 44: 874-877. [DOI: 10.1007/s001250100546]

98. Coward RJ, Welsh GI, Yang J, Tasman C, Lennon R, Koziell A, Satchell S, Holman GD, Kerjaschki D, Tavaré JM, Mathieson PW, Saleem MA.The human glomerular podocyte is a novel target for insulin action. Diabetes 2005; 54: 3095-3102. [PMID: 16249431]

99. Coward RJ, Welsh GI, Koziell A, Hussain S, Lennon R, Ni L, Tavaré JM, Mathieson PW, Saleem MA.Nephrin is critical for the action of insulin on human glomerular podocytes. Diabetes 2007; 56: 1127-1135. [DOI: 10.2337/db06-0693]

100. Xu ZG, Ryu DR, Yoo TH, Jung DS, Kim JJ, Kim HJ, Choi HY, Kim JS, Adler SG, Natarajan R, Han DS, Kang SW.P-Cadherin is decreased in diabetic glomeruli and in glucose-stimulated podocytes in vivo and in vitro studies. Nephrol Dial Transplant 2005; 20: 524-531. [DOI: 10.1093/ndt/gfh642]

101. Rincon-Choles H, Vasylyeva TL, Pergola PE, Bhandari B, Bhandari K, Zhang JH, Wang W, Gorin Y, Barnes JL, Abboud HE.ZO-1 expression and phosphorylation in diabetic nephropathy. Diabetes 2006; 55: 894-900. [PMID: 16567508]

102. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R,Mundel P, Smith PL, Clapham DE, Pollak MR.TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nature genetics 2005; 37: 739-744. [DOI: 10.1038/ng1592]

103. Sonneveld R, van der Vlag J, Baltissen MP, Verkaart SA, Wetzels JF, Berden JH, Hoenderop JG, Nijenhuis T.Glucose specifically regulates TRPC6 expression in the podocyte in an AngII-dependent manner. The American journal of pathology 2014; 184: 1715-1726. [DOI: 10.1016/j.ajpath.2014.02.008]

104. Ilatovskaya DV, Staruschenko A. TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases. American journal of physiology 2015; 309: F393-397. [DOI: 10.1152/ajprenal.00186.2015]

105. Ilatovskaya DV, Levchenko V, Lowing A, Shuyskiy LS, Palygin O, Staruschenko A.Podocyte injury in diabetic nephropathy: implications of angiotensin II-dependent activation of TRPC channels. Scientific reports 2015; 5: 17637. [DOI: 10.1038/srep17637]

106. Dietrich A, Chubanov V, Gudermann T. Renal TRPathies. J Am Soc Nephrol 2010; 21: 736-744. [DOI: 10.1681/ASN.2009090948]

107. Moller CC, Flesche J, Reiser J. Sensitizing the Slit Diaphragm with TRPC6 ion channels. J Am Soc Nephrol 2009; 20: 950-953. [DOI: 10.1681/ASN.2008030329]

108. Liu BC, Song X, Lu XY, Li DT, Eaton DC, Shen BZ, Li XQ, Ma HP.High glucose induces podocyte apoptosis by stimulating TRPC6 via elevation of reactive oxygen species. Biochimica et biophysica acta 2013; 1833: 1434-1442. [DOI: 10.1016/j.bbamcr.2013.02.031]

109. Thilo F, Lee M, Xia S, Zakrzewicz A, Tepel M.High glucose modifies transient receptor potential canonical type 6 channels via increased oxidative stress and syndecan-4 in human podocytes. Biochemical and biophysical research communications 2014; 450: 312-317. [DOI: 10.1016/j.bbrc.2014.05.116]

Peer reviewer: Rong Ma

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