title: The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy.
abstract: Progressive renal injury in diabetes mellitus leads to major morbidity and mortality. The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among these is transforming growth factor-beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the two hallmarks of diabetic renal disease. In cell culture, high ambient glucose increases TGF-beta mRNA and protein in proximal tubular, glomerular epithelial, and mesangial cells. Neutralizing anti-TGF-beta antibodies prevent the hypertrophic and matrix stimulatory effects of high glucose in these cells. In experimental and human diabetes mellitus, several reports describe overexpression of TGF-beta in the glomeruli and tubulointerstitium. We demonstrate that short-term treatment of diabetic mice with neutralizing monoclonal antibodies against TGF-beta significantly reduces kidney weight and glomerular hypertrophy and attenuates the increase in extracellular matrix mRNAs. Long-term treatment of diabetic mice further improves the renal pathology and also ameliorates the functional abnormalities of diabetic nephropathy. Finally, we provide evidence that the renal TGF-beta system is significantly up-regulated in human diabetes. The kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation whereas the kidney of a non-diabetic subject extracts TGF-beta1 from the circulation. The data we review here strongly support the hypothesis that elevated production or activity of the TGF-beta system mediates diabetic renal hypertrophy and extracellular matrix expansion.
authors.affiliation: Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, Philadelphia 19104-6144, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: S W
authors.initials: SW
authors.lastname: Hong
authors.forename: M C
authors.initials: MC
authors.lastname: Iglesias-de la Cruz
authors.forename: M
authors.initials: M
authors.lastname: Isono
authors.forename: A
authors.initials: A
authors.lastname: Casaretto
authors.forename: F N
authors.initials: FN
authors.lastname: Ziyadeh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D007668:Kidney / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D016212:Transforming Growth Factor beta