Under control of the Ren-1(c) promoter, locally produced transforming growth factor-β1 induces accumulation of glomerular extracellular matrix in transgenic mice

Lise Wogensen, Camilla Birch Nielsen, Peter Hjorth, Lars Melholt Rasmussen, Arne Høj Nielsen, Kenneth Gross, Nora Sarvetnick, Thomas Ledet

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Abstract

Our purpose was to elucidate the hypothesis that paracrine-produced transforming growth factor (TGF)β1 regulates the accumulation of extracellular matrix (ECM) in renal glomeruli, a hallmark of diabetic nephropathy. To produce TGF-β1 from the juxtaglomerular apparatus in mouse kidneys, we cloned a mouse Ren-1(c) promoter fragment (-4.100 to +6 base pairs) upstream of porcine TGF-β1 (pTGF-β1) cDNA, mutated to ensure secretion of biologically active TGF-β1. The resulting transgenic mice had significantly more TGF-β1 in their kidneys than was in those of nontransgenic controls, as confirmed by immunohistochemistry, and the production of TGF-β1 was enhanced in vivo by captopril-induced stimulation of the Ren-1(c) promoter. Overproduction of pTGF-β1 close to the glomerulus resulted in a local accumulation of ECM, composed partly of collagen type IV and laminin, and thickening of the basement membrane, characteristic features of diabetic nephropathy. Interstitial accumulation of ECM and signs of tubular atrophy were present only in older mice (>5 months of age). Results from in situ hybridization and immunohistochemistry suggest that pTGF-β1 stimulated the production of endogenous TGF-β1 along collecting ducts and connecting tubules. The increased amount of biologically active TGF-β1, transgenic as well as endogenous, was corroborated by heightened proteoglycan synthesis from incubated kidney slices. This transgenic model demonstrates that sustained local expression of TGF-β1 leads to glomerulopathy. We conclude that autocrine- or paracrine-produced TGF-β1 may play a role in the development of glomerular diseases, such as diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)182-192
Number of pages11
JournalDiabetes
Volume48
Issue number1
DOIs
StatePublished - Jan 1 1999

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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