Expression of TGF-B is elevated in the renal cortex of SHR/N-corpulent rats with diabetic nephropathy.

Diabetic nephropathy is characterized by glomerular mesangial expansion with accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis, and interstitial fibrosis. TGF-B, a key factor involved in ECM production and tissue repair, has been implicated in the pathogenesis of diabetic renal lesions. We investigated TGF-B expression in kidneys of SHR/N-corpulent (cp) rats, a genetic model of type 2 diabetes and hypertension with renal lesions resembling human diabetic nephropathy. Expression of TGF-B protein was assessed by immunohistochemistry using a polyclonal rabbit antibody which recognizes extracellular TGF-B in kidneys of 6-8 month old obese male SHR/N-cp rats (n=5) and lean controls (n=5). Rats were fed 54% carbohydrate diet containing 18% sucrose and 36% starch. Renal morphology was evaluated for glomerular lesions of mesangial expansion and sclerosis (MES). A tubulointerstitial score (TIS), an index of severity of tubulointerstitial lesions, e.g., tubular atrophy, cellular infiltration, and interstitial fibrosis was assigned. Morphologic analysis showed that the number of MES and TIS were higher in kidneys of obese than in lean rats (MES, 31±5% vs 4±1%, p<.01; TIS, +2.2±0.4 vs +0.5±0.2, p<.01). A 4-fold increase of TGF-B immunostaining in the renal cortex (expressed as number of foci of interstitial staining) was found in kidneys of obese rats compared to lean rats (p<.02). Treatment of obese rats (n=5) with the ACE inhibitor perindopril for 3 months reduced the glomerular lesions, TIS, and the amount of TGF-B staining in renal cortex. We conclude that 1) TGF-B protein is elevated in the renal parenchyma of obese SHR/N-cp rats with diabetic nephropathy; and 2) treatment of hypertension with perindopril ameliorates the renal lesions and the increased TGF-B expression.