Increased glomerular and tubular expression of transforming growth factor-beta 1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse

Citation
Sw. Hong et al., Increased glomerular and tubular expression of transforming growth factor-beta 1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse, AM J PATH, 158(5), 2001, pp. 1653-1663
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Journal title
AMERICAN JOURNAL OF PATHOLOGY
ISSN journal
0002-9440 → ACNP
Volume
158
Issue
5
Year of publication
2001
Pages
1653 - 1663
Database
ISI
SICI code
0002-9440(200105)158:5<1653:IGATEO>2.0.ZU;2-2
Abstract
Activation of the renal transforming growth factor-beta (TGF-beta) system l ikely mediates the excess production of extracellular matrix in the diabeti c kidney. To establish the role of the TGF-beta system in type 2 diabetic n ephropathy, we examined the intrarenal localization and expression of the T GF-beta1 isoform, the TGF-beta type II receptor, and the Smad signaling pat hway in the 16-week-old db/db mouse, a genetic model of type 2 diabetes tha t exhibits mesangial matrix expansion, glomerular basement membrane thicken ing, and renal insufficiency that closely resemble the human disease. Compa red with its nondiabetic db/m litter-mate, the db/db mouse showed significa ntly increased TGF-beta1 mRNA expression by in situ hybridization in both g lomerular and tubular compartments, Likewise, TGF-beta1 protein, by immunoh istochemical staining, was increased in both renal compartments, but the fr actional expression of TGF-beta1 protein was less than that of the mRNA in the glomerulus.. In situ hybridization and immunohistochemical staining for the TGF-beta type II receptor revealed concordant and significant increase s of both mRNA and protein in the glomerular and tubular compartments of di abetic animals. Finally, immunohistochemistry showed preferential accumulat ion of Smad3 in the nuclei of glomerular and tubular cells in diabetes. The complementary technique of Southwestern histochemistry using a labeled Sma d-binding element demonstrated increased binding of nuclear proteins to Sma d-binding element, indicating active signaling downstream of the TGF-beta s timulus. We therefore propose that the TGF-beta system is up-regulated at t he ligand, receptor, and signaling levels throughout the renal cortex in th is animal model of type 2 diabetes. Our findings suggest that the profibrot ic effects of TGF-beta may underlie the progression to glomerulosclerosis a nd tubulointerstitial fibrosis that characterize diabetic nephropathy.