title: Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats.
abstract: Aldosterone itself has been reported to participate in mediating renal injury, and it was confirmed that the aldosterone synthase CYP11B2 gene, protein, and aldosterone production are locally present in the kidney. To test the hypothesis that a mineralocorticoid receptor antagonist might ameliorate diabetic nephropathy and the inhibition of renal CYP11B2 expression might be associated with these renoprotective effects, spironolactone (50 mg/kg/day) was administered by gavage to uninephrectomized diabetic rats for 3 weeks. Streptozotocin (55 mg/kg, i.v.) significantly increased urinary protein excretion and collagen deposition in glomerular and tubulointerstitial areas in the kidney, which were attenuated by spironolactone treatment. RT-PCR and Western blot analysis revealed that the expression of mRNA for collagen I/IV, transforming growth factor-beta, NADPH oxidase and mineralocorticoid receptor and the mineralocorticoid receptor protein in the kidney was enhanced in the uninephrectomized diabetic rat kidney and that the overexpression of these molecules was suppressed by spironolactone. Renal angiotensin converting enzyme was activated and overexpressed in diabetic rats, and spironolactone inhibited these changes. We demonstrated that spironolactone prevented the streptozotocin-induced increase in the renal CYP11B2 mRNA content. Controlling blood glucose level with insulin also attenuated the renal expression of mRNA for CYP11B2. On the other hand, the treatment of spironolactone in the present study did not affect blood glucose level or blood pressure in uninephrectomized streptozotocin-induced diabetic rats. These results suggest that spironolactone exerted renoprotective effects in uninephrectomized streptozotocin-induced diabetic rats and inhibited local renin-angiotensin-aldosterone system, such as the ACE expression and the hyperglycemia-induced overexpression of CYP11B2, in the kidney.
authors.affiliation: Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Taira
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Masafumi
authors.initials: M
authors.lastname: Murakami
authors.forename: Ikumi
authors.initials: I
authors.lastname: Iga
authors.forename: Ryoko
authors.initials: R
authors.lastname: Serizawa
authors.forename: Shoko
authors.initials: S
authors.lastname: Murata
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009392:Nephrectomy; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012077:Renal Artery / Q000601:surgery; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013148:Spironolactone / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D016212:Transforming Growth Factor beta; D013148:Spironolactone; D019405:Cytochrome P-450 CYP11B2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D007703:Peptidyl-Dipeptidase A