This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Jun Yuan Articles by Yan Bao Search for Related Content PubMed PubMed Citation Articles by Jun Yuan, Articles by Yan Bao, Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetic Kidney Problems Hazardous Substances DB MALONALDEHYDE SPIRONOLACTONE Social Bookmarking                         What's this?

Beneficial effects of spironolactone on glomerular injury in streptozotocin-induced diabetic rats

Department of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China

Ruhan Jia

Department of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China, stfgp{at}126.com

Yan Bao

Department of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China

Introduction. To investigate the beneficial effects of spironolactone (SPL) on glomerular injury in streptozotocin (STZ)-induced diabetic rats and the possible mechanism.

Methods and results. STZ-induced diabetic rats were divided into control group, STZ group, and SPL group. Glomerular morphology was observed by light microscopy after the rats were sacrificed after 30 days treatment.The mRNA expressions of transforming growth factor-beta 1 (TGF-β1) and type-1 plasminogen activator inhibitor (PAI-1) in renal cortex were measured by transcription-polymyerase chain reaction (RT-PCR).The protein expressions of PAI-1, fibronectin (FN) and TGF-β1 were detected by western blotting and immunohistochemistry respectively. In addition, levels of malondialdehyde (MDA) and the activity of antioxidants including superoxide diamutase (SOD), glutathione peroxidase (GSH-P _X) in the cortex of kidney were measured.

Results. In untreated diabetic rats, the glomerular volume, the expression of FN and the urinary albumin excretion increased. The mRNA and protein expression of PAI-1 and TGF-β ₁ significantly increased in the STZ group. Treatment with SPL partially reversed these changes. Meanwhile, elevated MDA levels as well as decreased SOD and GSH-P_X activities in the cortex of kidney were significantly ameliorated in the treated group.

Conclusion. SPL ameliorates the glomerular injury in STZ-induced early diabetic renal injury, which is closely related with the reduction of PAI-1 and TGF-β1 expression and the attenuation of oxidative stress.

Key Words: aldosterone • diabetic nephropathy • oxidative stress transforming growth factor-beta1 • type-1 plasminogen activator inhibitor

References

• Sakharova OV, Taal MW, Brenner BM Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor. Curr Opin Nephrol Hypertens 2001;10:727-38.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabetes 2001;109(suppl 2):S424-S437.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Eddy AA Molecular basis of renal fibrosis. Pediatr Nephrol 2000;15:290-301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Vaughan DE Angiotensin, fibrinolysis, and vascular homeostasis. Am J Cardiol 2001;87:C18-C24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Eddy AA Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 2002;283:F209-F220.[Abstract/Free Full Text]
• Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991;88:1067-72.[Web of Science][Medline] [Order article via Infotrieve]
• Nicholas SB, Aguiniga E., Ren Y. et al. Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Kidney Int 2005;67:1297-307.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Li H., Jiang T., Lin Y. et al. HGF Protects Rat Mesangial Cells from High-Glucose-Mediated Oxidative Stress. Am J Nephrol 2006;26:519-30.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Palm F. Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy. Clin Exp Pharmacol Physiol 2006;33:997-1001.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005;16(suppl 1):S30-S33.[Abstract/Free Full Text]
• Umezono T., Toyoda M., Kato M. et al. Glomerular expression of CTGF, TGF-beta 1 and type IV collagen in diabetic nephropathy. J Nephrol 2006;19:751-7.[Web of Science][Medline] [Order article via Infotrieve]
• Ha H., Lee HB Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology (Carlton), 2005;10:(suppl):S7-S10.[CrossRef]
• Fujisawa G., Okada K., Muto S. et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004;66:1493-502.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Miric G., Dallemagne C., Endre Z. et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol 2001;133:687-94.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Sato A., Hayashi K., Saruta T. Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens 2005;18:44-9.[Web of Science][Medline] [Order article via Infotrieve]
• Schjoedt KJ, Rossing K., Juhl TR et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005;68:2829-36.[CrossRef][Medline] [Order article via Infotrieve]
• Guo C., Martinez-Vasquez D., Mendez GP et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology 2006;147:5363-73.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Han KH, Kang YS, Han SY et al. Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats. Kidney Int 2006;70:111-20.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Han SY, Kim CH, Kim HS et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 2006;17:1362-72.[Abstract/Free Full Text]
• Sawathiparnich P., Kumar S., Vaughan DE et al. Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab 2002;87:448-52.[Abstract/Free Full Text]
• Brown NJ, Nakamura S., Ma L. et al. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 2000;58:1219-27.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Ma J., Weisberg A., Griffin JP et al. Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int 2006;69:1064-72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• van Bamme B., Koudstaal J. Measuring glomerular diameters in tissue sections. Virchows Arch A Pathol Anat Histol 1976;369:283-91.[CrossRef][Medline] [Order article via Infotrieve]
• de Gasparo M., Joss U., Ramjoue HP et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987;240:650-6.[Abstract/Free Full Text]
• Ziyadeh FN, Sharma K. Overview: combating diabetic nephropathy. J Am Soc Nephrol 2003;14:1355-7.[Free Full Text]
• Chen LL, Zhang JY, Wang BP Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor-1. Vascul Pharmacol 2006;44:309-15.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Lee HB, Ha H. Plasminogen activator inhibitor-1 and diabetic nephropathy. Nephrology (Carlton). 2005;10 (Suppl):S11-S13.[CrossRef]
• Collins SJ, Alexander SL, Lopez-Guisa JM et al. Plasminogen activator inhibitor-1 deficiency has renal benefits but some adverse systemic consequences in diabetic mice. Nephron Exp Nephrol 2006;104:e23-e34.[CrossRef][Medline] [Order article via Infotrieve]
• Beisswenger PJ, Drummond KS, Nelson RG et al. Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. Diabetes 2005;54:3274-81.[Abstract/Free Full Text]
• Chang JM, Kuo MC, Kuo HT et al. Increased glomerular and extracellular malondialdehyde levels in patients and rats with diabetic nephropathy. J Lab Clin Med 2005;146:210-15.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Satoh M., Fujimoto S., Haruna Y. et al. NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Renal Physiol 2005;288:F1144-F1152.[Abstract/Free Full Text]
• Koya D., Hayashi K., Kitada M. et al.Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol 2003;14:S250-S253.[Abstract/Free Full Text]
• Yin X., Zhang Y., Yu J. et al. The antioxidative effects of astragalus saponin I protect against development of early diabetic nephropathy. J Pharmacol Sci 2006;101:166-73.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Vasavada N., Agarwal R. Role of oxidative stress in diabetic nephropathy. Adv Chronic Kidney Dis 2005;12:146-54.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Sun Y., Zhang J., Lu L. et al. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol 2002;161:1773-81.[Abstract/Free Full Text]
• Virdis A., Neves MF, Amiri F. et al. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 2002;40:504-10.[Abstract/Free Full Text]
• Takebayashi K., Matsumoto S., Aso Y. et al. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab 2006;91:2214-7.[Abstract/Free Full Text]
• Goldfarb S., Ziyadeh FN TGF-beta: a crucial component of the pathogenesis of diabetic nephropathy. Trans Am Clin Climatol Assoc 2001;112:27-32.[Medline] [Order article via Infotrieve]
• Tamaki K., Okuda S. Role of TGF-beta in the progression of renal fibrosis. Contrib Nephrol 2003;139:44-65.[Web of Science][Medline] [Order article via Infotrieve]
• Lane PH, Snelling DM, Langer WJ Streptozocin diabetes elevates all isoforms of TGF-beta in the rat kidney. Int J Exp Diabetes Res 2001;2:55-62.[Medline] [Order article via Infotrieve]
• Lopez-Casillas F. [Transforming growth factor-beta (TGF-beta), keystone in diabetic nephropathy]. Rev Invest Clin 2000;52:487-90.[Web of Science][Medline] [Order article via Infotrieve]
• Wilson HM, Reid FJ, Brown PA et al. Effect of transforming growth factor-beta 1 on plasminogen activators and plasminogen activator inhibitor-1 in renal glomerular cells. Exp Nephrol 1993;1:343-50.[Web of Science][Medline] [Order article via Infotrieve]
• Dennler S., Itoh S., Vivien D. et al. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998;17:3091D -100.[CrossRef]
• Krag S., Danielsen CC, Carmeliet P. et al. Plasminogen activator inhibitor-1 gene deficiency attenuates TGF-beta1induced kidney I disease. Kidney Int 2005;68:2651-66.matrix[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Baricos WH, Reed JC, Cortez SL Extracellular matrix degradation by cultured mesangial cells: mediators and modulators. Exp Biol Med (Maywood) 2003;228:1018-22.[Abstract/Free Full Text]
• Du XL, Edelstein D., Rossetti L. et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000;97:12222-6.[Abstract/Free Full Text]
• Zhao W., Spitz DR, Oberley LW et al. Redox modulation of the pro-fibrogenic mediator plasminogen activator inhibitor-1 following ionizing radiation. Cancer Res 2001;61:5537-43.[Abstract/Free Full Text]
• Cheng JJ, Chao YJ, Wung BS et al. Cyclic strain-induced plasminogen activator inhibitor-1 (PAI-1) release from endothelial cells involves reactive oxygen species. Biochem Biophys Res Commun 1996;225:100-05.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Rerolle JP, Hertig A., Nguyen G. et al. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int 2000;58:1841-50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Baricos WH, Cortez SL, Deboisblanc M. et al. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J Am Soc Nephrol 1999;10:790-5.[Abstract/Free Full Text]
• Vulin AI, Stanley FM Oxidative stress activates the plasminogen activator inhibitor type 1 (PAI-1) promoter through an AP-1 response element and cooperates with insulin for additive effects on PAI-1 transcription. J Biol Chem 2004;279:25172-8.[Abstract/Free Full Text]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 8, No. 3, 118-126 (2007)
DOI: 10.3317/jraas.2007.014


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Jun Yuan Articles by Yan Bao Search for Related Content PubMed PubMed Citation Articles by Jun Yuan, Articles by Yan Bao, Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetic Kidney Problems Hazardous Substances DB MALONALDEHYDE SPIRONOLACTONE Social Bookmarking                         What's this?