THE RENAL TGF-BETA SYSTEM IN THE DB DB MOUSE MODEL OF DIABETIC NEPHROPATHY/

The prosclerotic cytokine transforming growth factor beta 1 (TGF-beta( 1)) has been causally implicated in renal pathobiology in diabetes. We sought evidence that the TGF-beta system participates in the nephropa thic process in the db/db mouse, a hyperinsulinemic model of genetic d iabetes that develops abnormalities in renal morphology and function t hat parallel those in human diabetic nephropathy. In support of this h ypothesis, we found that steady state levels of mRNA encoding the TGF- beta type II receptor were significantly increased in renal cortex fro m db/db diabetic mice. Additionally, the translated TGF-beta type II r eceptor protein, assessed by immunoblot, also was increased in diabeti c kidneys. However, in contrast to rodents with insulin-deficient diab etes, steady state levels of mRNA encoding TGF-beta 1 in the renal cor tex of diabetic db/db mice did not differ from those in cortex from no ndiabetic (db/m) littermate controls. Further, concentrations of TGF-b eta protein, measured by immunoassay and bioassay, were significantly lower in extracts prepared from renal cortex of diabetic animals compa red with those from nondiabetic controls. Urine and serum concentratio ns of immunoreactive TGF-beta(1) also were reduced in diabetic mice. T he findings are consistent with upregulation of TGF-beta type II recep tor activity as a consequence of hyperglycemia in the hyperinsulinemic db/db mouse and suggest that hyperinsulinemia inhibits TGF-beta 1 pro duction. The results further suggest that type II receptor upregulatio n is a contributing factor to the increased gene expression of renal c ortical mRNAs encoding the extracellular matrix proteins fibronectin a nd alpha I (IV) collagen and to the renal abnormalities observed in th is animal model.