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The renoprotective effect of captopril on progression of diabetic nephropathy was demonstrated by the Collaborative Study Group Captopril Trial and might be independent of blood pressure. Because angiotensin II is known to stimulate the prosclerotic cytokine, transforming growth factor-beta (TGF-beta), we postulated that the renoprotective effect may be due to inhibition of TGF-beta1 production. TGF-beta1 levels were measured in serum at baseline and 6 months from patients in the captopril trial. TGF-beta1 analyses were performed on all available patient sera. Analysis was performed between the percent change in TGF-beta1 levels during the first 6 months versus the percent change in glomerular filtration rate (GFR) in the subsequent 2 years. TGF-beta1 levels increased by 11% (P = 0. 003) in the placebo group (n = 24), whereas there was a decrease of 14% (P = 0.01) in the captopril group (n = 34). There was an inverse correlation between the percent change in TGF-beta1 levels during the first 6 months and the percent change in GFR over the ensuing 2-year period in patients from both the placebo (r = -0.55, P = 0. 005) and captopril groups (r = -0.45, P = 0.008). In patients with initial GFR below 75 mL/min, there was an even stronger correlation in percent change in TGF-beta1 levels and percent change in GFR in both placebo (n = 9, r = -0.69, P = 0.03) and captopril groups (n = 21, r = -0.73, P = 0.0001). Our data suggest that captopril decreases TGF-beta1 levels in diabetic nephropathy and that changes in TGF-beta1 levels may predict the course of diabetic nephropathy.

The prosclerotic cytokine transforming growth factor beta 1 (TGF-beta1) has been causally implicated in renal pathobiology in diabetes. We sought evidence that the TGF-beta system participates in the nephropathic process in the db/db mouse, a hyperinsulinemic model of genetic diabetes that develops abnormalities in renal morphology and function that parallel those in human diabetic nephropathy. In support of this hypothesis, we found that steady state levels of mRNA encoding the TGF-beta type II receptor were significantly increased in renal cortex from db/db diabetic mice. Additionally, the translated TGF-beta type II receptor protein, assessed by immunoblot, also was increased in diabetic kidneys. However, in contrast to rodents with insulin-deficient diabetes, steady state levels of mRNA encoding TGF-beta1 in the renal cortex of diabetic db/db mice did not differ from those in cortex from nondiabetic (db/m) littermate controls. Further, concentrations of TGF-beta protein, measured by immunoassay and bioassay, were significantly lower in extracts prepared from renal cortex of diabetic animals compared with those from nondiabetic controls. Urine and serum concentrations of immunoreactive TGF-beta1 also were reduced in diabetic mice. The findings are consistent with upregulation of TGF-beta type II receptor activity as a consequence of hyperglycemia in the hyperinsulinemic db/db mouse and suggest that hyperinsulinemia inhibits TGF-beta1 production. The results further suggest that type II receptor upregulation is a contributing factor to the increased gene expression of renal cortical mRNAs encoding the extracellular matrix proteins fibronectin and alpha 1 (IV) collagen and to the renal abnormalities observed in this animal model.