THE ROLE OF TGF-β1 IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY EXPERIMENTALLY INDUCED BY STREPTOZOTOCIN AND THE NEPHROPROTECTIVE EFFECTS OF CANDESARTAN

  • Jasmina Trojacanec Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss Cyril and Methodius University in Skopje, North Macedonia
  • Kristina Pavlovska Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Emilija Shikole Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Nikola Kolovchevski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Bojan Labachevski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Aleksandar Nikodinovski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Krume Jakjovski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Igor Kikerkov Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Marija Petrusevska Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Panche Zdravkovski Department of Pathology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia
  • Dimche Zafirov Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, North Macedonia

Abstract

Diabetic nephropathy (DN) stands as a prevalent and severe complication of diabetes mellitus (DM), lacking adequate medical therapy. The molecular mechanisms contributing to glomerular membrane damage involve the overactivity of angiotensin II, heightened expression of nephrin, vascular endothelial growth factor (VEGF), and notably, intraglomerular transforming growth factor TGF-β1. Pharmaceutical treatments targeting hemodynamic disturbances in diabetic nephropathy, such as ACE inhibitors and angiotensin receptor blockers (ARBs), hold promise for DN therapy. This study aimed to assess the role of intraglomerular TGF-β expression in experimentally induced DN in rats and explore the nephroprotective effects of candesartan. Diabetes mellitus was induced through a single intraperitoneal injection of streptozotocin (STZ) at 60 mg/kg, and DN was allowed to develop over four weeks. DM rats were randomly assigned to two groups: STZ (untreated) and STZ+CAN (treated with candesartan at 5 mg/kg/day from week 4 to week 12). STZ administration led to a substantial increase in TGF-β1 expression in the glomeruli, exceeding control levels by 5-6 times. Candesartan treatment demonstrated a significant reduction in glomerular proliferation and subsequent expansion of the mesangial matrix, suggesting a potential mechanism by which these drugs achieve therapeutic effects.


Key words: Streptozotocin, Diabetic nephropathy, TGF-β1, Candesartan, Rats.


 

References

1. Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC: Structural functional relationships in diabetic nephropathy. J Clin Invest 1984; 74: 1143–1155.
2. Ziyadeh FN, Goldfarb S: The renal tubulointerstitium in diabetes mellitus. Kidney Int 1991; 39: 464–475.
3. Remuzzi G and Bertani T: Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–1456.
4. Patari A, Forsblom C, Havana M, Taipale H, Groop PH, Holthofer H: Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes 2003; 52: 2969-2974.
5. 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 Apr;52(4):1023-30.
6. 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.
7. Benigni A, Gagliardini E, Remuzzi G. Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte dysfunction and slit diaphragm protein arrangement. Semin Nephrol. 2004 Mar;24(2):131-40.
8. Langham RG, Kelly DJ, Cox AJ, Thomson NM, Holthofer 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.
9. Gassler N, Elger M, Kränzlin B, Kriz W, Gretz N, Hähnel B, Hosser H, Hartmann I. Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat. Kidney Int. 2001 Jul;60(1):106-16.
10. Coimbra TM, Janssen U, Gröne HJ, Ostendorf T, Kunter U, Schmidt H, Brabant G, Floege J. Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int. 2000 Jan;57(1):167-82.
11.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.
12.Kelly DJ, Aaltonen P, Cox AJ, Rumble JR, Langham R, Panagiotopoulos S, Jerums G, Holthofer 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.
13. Ding G, Reddy K, Kapasi AA, Franki N, Gibbons N, Kasinath BS, Singhal PC: Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Renal Physiol 2002; 283: F173-F180.
14. Schiffer M, Mundel P, Shaw AS, Bottinger EP: A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem 2004; 279: 37004-37012.
15. Chen S, Jim B, Ziyadeh FN: Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol, 2003; 23: 532-543.
16. Ziyadeh FN: Mediators of diabetic renal disease: the case for TGF-β as the major mediator. J Am Soc Nephrol 2004; 15 (Suppl. 1): S55-S57.
17. Pavenstadt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev 2003; 83: 253–307.
18. Mizuno M, Sada T, Kato M, Koike H. Renoprotective effects of blockade of angiotensin II AT1 receptors in an animal model of type 2 diabetes. Hypertens Res. 2002 Mar;25(2):271-8.
19. Pugsley MK. The angiotensin-II (AT-II) receptor blocker olmesartan reduces renal damage in animal models of hypertension and diabetes. Proc West Pharmacol Soc. 2005; 48:35-8.
20. Temel HE, Akyuz F. The effects of captopril and losartan on erythrocyte membrane Na+/K(+)-ATPase activity in experimental diabetes mellitus. J Enzyme Inhib Med Chem. 2007 ;22(2):213-7.
21. Schmieder RE. Renin inhibitors: optimal strategy for renal protection. Curr Hypertens Rep. 2007 Nov;9(5):415-21.
22.Wang S-N, Hirschberg R: Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis. Am J Physiol Renal Physiol 2000; 278: F554-F560.
23. Wang S-N, LaPage J, Hirschberg R: Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int 2000 (а); 57: 1002-1014.
24. Ziyadeh FN, Hoffman BB, Han DC, Iglesias-de la Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K: Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 2000; 97: 8015-8020.
25. Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS: Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest 1996; 74: 991-1003.
26. Dessapt C, Baradez MO, Hayward A, Dei Cas A, Thomas SM, Viver G, Gnudi L Mechanical forces and TGFß1 reduce podocyte adhesion through α3ß1 integrin downregulation. Nephrol Dial Transplant. 2009; 24:2645–2655.
27. Lee HS, Song CY Effects of TGF-ß on podocyte growth and disease progression in proliferative podocytopathies. Kidney Blood Press Res 2010; 33:24–29.
Published
2023-12-27
How to Cite
TROJACANEC, Jasmina et al. THE ROLE OF TGF-β1 IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY EXPERIMENTALLY INDUCED BY STREPTOZOTOCIN AND THE NEPHROPROTECTIVE EFFECTS OF CANDESARTAN. Journal of Morphological Sciences, [S.l.], v. 6, n. 3, p. 234-245, dec. 2023. ISSN 2545-4706. Available at: <https://jms.mk/jms/article/view/vol6no3-30>. Date accessed: 21 dec. 2024.
Citation Formats
Issue
Vol 6 No 3 (2023): JMS
Section
Articles