title: Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats.
abstract: Administration of spironolactone provides a beneficial effect in various animal models of renal injury. In this study, we investigated whether spironolactone prevents the progression of diabetic nephropathy through reduction of connective tissue growth factor (CTGF) synthesis in type II diabetic rats. In addition, we evaluated the effect of aldosterone and spironolactone on CTGF and collagen production in cultured cells. Renal functional and morphologic changes were examined in Otsuka Long-Evans Tokushima Fatty rats with or without spironolactone treatment (20 mg/kg/day) for 8 months, as well as in non-diabetic age-matched Long-Evans Tokushima Otsuka rats. Spironolactone treatment did not induce any significant differences in body weight, kidney/body weight ratio, serum creatinine concentration, blood glucose levels, or systolic blood pressure. However, urinary protein and albumin excretion were significantly decreased in the spironolactone treatment group, which was associated with amelioration of glomerulosclerosis. In addition, renal CTGF, collagen synthesis demonstrated marked decreases in the spironolactone treatment group. In cultured MC and PTC, aldosterone induced significant increases in CTGF gene expression and protein synthesis associated with increased collagen synthesis, which was abolished by prior treatment with spironolactone. However, aldosterone treatment did not induce transforming growth factor (TGF)-beta1 overproduction, and inhibition of TGF-beta1 by neutralization of TGF-beta1 protein did not significantly prevent aldosterone-induced CTGF production. These results suggest that the antifibrotic effects of spironolactone may be mediated by CTGF through a TGF-beta1-independent pathway in this animal model of diabetic nephropathy.
authors.affiliation: Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Han
authors.forename: Y S
authors.initials: YS
authors.lastname: Kang
authors.forename: S-Y
authors.initials: SY
authors.lastname: Han
authors.forename: Y H
authors.initials: YH
authors.lastname: Jee
authors.forename: M H
authors.initials: MH
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Han
authors.forename: H K
authors.initials: HK
authors.lastname: Kim
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: D R
authors.initials: DR
authors.lastname: Cha
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone; D000818:Animals; D024141:Collagen Type IV / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D013148:Spironolactone / Q000627:therapeutic use*
chemical_list: C526316:CCN2 protein, rat; D024141:Collagen Type IV; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D000450:Aldosterone; D042842:11-beta-Hydroxysteroid Dehydrogenases