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01.02.2016 | Article

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

verfasst von: Jay C. Jha, Vicki Thallas-Bonke, Claudine Banal, Stephen P. Gray, Bryna S. M. Chow, Georg Ramm, Susan E. Quaggin, Mark E. Cooper, Harald H. H. W. Schmidt, Karin A. Jandeleit-Dahm

Erschienen in: Diabetologia | Ausgabe 2/2016

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Abstract

Aims/hypothesis

Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage.

Methods

Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin.

Results

Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice.

Conclusions/interpretation

Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents.

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Roglic G, Unwin N, Bennett PH et al (2005) The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 28:2130–2135PubMedCrossRef

Molitch ME, DeFronzo RA, Franz MJ et al (2004) Nephropathy in diabetes. Diabetes Care 27(Suppl 1):S79–s83PubMed

Bjorn SF, Bangstad HJ, Hanssen KF et al (1995) Glomerular epithelial foot processes and filtration slits in IDDM patients. Diabetologia 38:1197–1204PubMedCrossRef

Eid AA, Gorin Y, Fagg BM et al (2009) Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes 58:1201–1211PubMedPubMedCentralCrossRef

Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354:1387–1401PubMedCrossRef

Calcutt NA, Cooper ME, Kern TS, Schmidt AM (2009) Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov 8:417–429PubMedCrossRef

Gill PS, Wilcox CS (2006) NADPH oxidases in the kidney. Antioxid Redox Signal 8:1597–1607PubMedCrossRef

Kaneto H, Katakami N, Kawamori D et al (2007) Involvement of oxidative stress in the pathogenesis of diabetes. Antioxid Redox Signal 9:355–366PubMedCrossRef

Jha JC, Gray SP, Barit D et al (2014) Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol 25:1237–1254PubMedPubMedCentralCrossRef

10.

Gorin Y, Block K, Hernandez J et al (2005) Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem 280:39616–39626PubMedCrossRef

11.

Holterman CE, Thibodeau JF, Towaij C et al (2014) Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression. J Am Soc Nephrol 25:784–797PubMedPubMedCentralCrossRef

12.

Brenner BM, Hostetter TH, Humes HD (1978) Molecular basis of proteinuria of glomerular origin. N Engl J Med 298:826–833PubMedCrossRef

13.

Palicz A, Foubert TR, Jesaitis AJ, Marodi L, McPhail LC (2001) Phosphatidic acid and diacylglycerol directly activate NADPH oxidase by interacting with enzyme components. J Biol Chem 276:3090–3097PubMedCrossRef

14.

Satoh M, Fujimoto S, Haruna Y et al (2005) NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Ren Physiol 288:F1144–F1152CrossRef

15.

Ding G, Reddy K, Kapasi AA et al (2002) Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Ren Physiol 283:F173–F180CrossRef

16.

Schiffer M, Bitzer M, Roberts IS et al (2001) Apoptosis in podocytes induced by TGF-β and Smad7. J Clin Invest 108:807–816PubMedPubMedCentralCrossRef

17.

Wolf G, Chen S, Ziyadeh FN (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54:1626–1634PubMedCrossRef

18.

Asaba K, Tojo A, Onozato ML et al (2005) Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 67:1890–1898PubMedCrossRef

19.

Susztak K, Raff AC, Schiffer M, Bottinger EP (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55:225–233PubMedCrossRef

20.

Watson AM, Li J, Schumacher C et al (2010) The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice. Diabetologia 53:192–203PubMedCrossRef

21.

Krege JH, Hodgin JB, Hagaman JR, Smithies O (1995) A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25:1111–1115PubMedCrossRef

22.

Chai Z, Dai A, Tu Y et al (2013) Genetic deletion of cell division autoantigen 1 retards diabetes-associated renal injury. J Am Soc Nephrol 24:1782–1792PubMedPubMedCentralCrossRef

23.

Lassila M, Seah KK, Allen TJ et al (2004) Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products. J Am Soc Nephrol 15:2125–2138PubMedCrossRef

24.

Mifsud SA, Allen TJ, Bertram JF et al (2001) Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade. Diabetologia 44:878–882PubMedCrossRef

25.

Sato S, Sasaki Y, Adachi A, Ghazizadeh M (2010) Validation of glomerular basement membrane thickness changes with aging in minimal change disease. Pathobiology 77:315–319PubMedCrossRef

26.

Koulis C, Chow BS, McKelvey M et al (2015) AT2R agonist, compound 21, is reno-protective against type 1 diabetic nephropathy. Hypertension 65:1073–1081PubMedCrossRef

27.

Doublier S, Salvidio G, Lupia E et al (2003) Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 52:1023–1030PubMedCrossRef

28.

Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Rollin BJ, Tesch GH (2006) Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int 69:73–80PubMedCrossRef

29.

Cooper ME, Mundel P, Boner G (2002) Role of nephrin in renal disease including diabetic nephropathy. Semin Nephrol 22:393–398PubMedCrossRef

30.

Cooper ME, Vranes D, Youssef S et al (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48:2229–2239PubMedCrossRef

31.

Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, Chen S (2006) Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 17:3093–3104PubMedCrossRef

32.

Thallas-Bonke V, Jha JC, Gray SP et al (2014) Nox-4 deletion reduces oxidative stress and injury by PKC-α-associated mechanisms in diabetic nephropathy. Physiol Rep 2, e12192PubMedPubMedCentralCrossRef

33.

Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4:39–45PubMedCrossRef

34.

Zhao QD, Viswanadhapalli S, Williams P et al (2015) NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation 131:643–655PubMedPubMedCentralCrossRef

35.

Bangstad HJ, Osterby R, Dahl-Jorgensen K, Berg KJ, Hartmann A, Hanssen KF (1994) Improvement of blood glucose control in IDDM patients retards the progression of morphological changes in early diabetic nephropathy. Diabetologia 37:483–490PubMedCrossRef

36.

Tervaert TW, Mooyaart AL, Amann K et al (2010) Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 21:556–563PubMedCrossRef

37.

Mac-Moune Lai F, Szeto CC, Choi PC et al (2004) Isolate diffuse thickening of glomerular capillary basement membrane: a renal lesion in prediabetes? Mod Pathol 17:1506–1512PubMedCrossRef

38.

Falk RJ, Scheinman JI, Mauer SM, Michael AF (1983) Polyantigenic expansion of basement membrane constituents in diabetic nephropathy. Diabetes 32(Suppl 2):34–39PubMedCrossRef

39.

Kim Y, Kleppel MM, Butkowski R, Mauer SM, Wieslander J, Michael AF (1991) Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Pathol 138:413–420PubMedPubMedCentral

40.

Kim J, Shon E, Kim CS, Kim JS (2012) Renal podocyte injury in a rat model of type 2 diabetes is prevented by metformin. Exp Diabetes Res 2012:210821PubMedPubMedCentral

41.

Montero A, Munger KA, Khan RZ et al (2000) F₂-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes. Kidney Int 58:1963–1972PubMedCrossRef

42.

Giorgi C, Agnoletto C, Baldini C et al (2010) Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid Redox Signal 13:1051–1085PubMedCrossRef

43.

Menne J, Meier M, Park JK et al (2006) Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo. Kidney Int 70:1456–1462PubMedCrossRef

44.

Menne J, Shushakova N, Bartels J et al (2013) Dual inhibition of classical protein kinase C-α and protein kinase C-β isoforms protects against experimental murine diabetic nephropathy. Diabetes 62:1167–1174PubMedPubMedCentralCrossRef

45.

Quack I, Woznowski M, Potthoff SA et al (2011) PKCα mediates β-arrestin2-dependent nephrin endocytosis in hyperglycemia. J Biol Chem 286:12959–12970PubMedPubMedCentralCrossRef

46.

Gorin Y, Cavaglieri RC, Khazim K et al (2015) Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am J Physiol Ren Physiol 308:F1276–F1287CrossRef

Titel: Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy
verfasst von: Jay C. Jha
Vicki Thallas-Bonke
Claudine Banal
Stephen P. Gray
Bryna S. M. Chow
Georg Ramm
Susan E. Quaggin
Mark E. Cooper
Harald H. H. W. Schmidt
Karin A. Jandeleit-Dahm
Publikationsdatum: 01.02.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3796-0

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