The renal TGF-β system in the db/db mouse model of diabetic nephropathy

Margo P. Cohen, Kumar Sharma, Jia Guo, Babiker O. Eltayeb, Fuad N. Ziyadeh

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The prosclerotic cytokine transforming growth factor beta 1 (TGF-β) has been causally implicated in renal pathobiology in diabetes. We sought evidence that the TGF-β 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-β type II receptor were significantly increased in renal cortex from db/db diabetic mice. Additionally, the translated TGF-β 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-β 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-β 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-β1 also were reduced in diabetic mice. The findings are consistent with upregulation of TGF-β type II receptor activity as a consequence of hyperglycemia in the hyperinsulinemic db/db mouse and suggest that hyperinsulinemia inhibits TGF-β1 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 I (IV) collagen and to the renal abnormalities observed in this animal model.

Original languageEnglish (US)
Pages (from-to)226-233
Number of pages8
JournalExperimental Nephrology
Volume6
Issue number3
DOIs
StatePublished - 1998
Externally publishedYes

Keywords

  • Diabetes
  • Diabetic nephropathy
  • Transforming growth factor beta
  • db/db mice

ASJC Scopus subject areas

  • Nephrology

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