Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat

Ariela Benigni, Carla Zoja, Daniela Corna, Cristina Zatelli, Sara Conti, Marco Campana, Elena Gagliardini, Daniela Rottoli, Cristina Zanchi, Mauro Abbate, Steve Ledbetter, Giuseppe Remuzzi

Research output: Contribution to journalArticle

Abstract

Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-β (TGF-β) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-β and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-β monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-β antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-β antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.

Original languageEnglish
Pages (from-to)1816-1824
Number of pages9
JournalJournal of the American Society of Nephrology
Volume14
Issue number7
DOIs
Publication statusPublished - Jul 1 2003

ASJC Scopus subject areas

  • Nephrology

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