Open AccessAn integrin antagonist ( MK ‐0429) decreases proteinuria and renal fibrosis in the ZSF 1 rat diabetic nephropathy model
Author(s) -
Zhou Xiaoyan,
Zhang Ji,
Haimbach Robin,
Zhu Wei,
MayerEzell Rosemary,
GarciaCalvo Margarita,
Smith Elizabeth,
Price Olga,
Kan Yanqing,
Zycband Emanuel,
Zhu Yonghua,
Hoek Maarten,
Cox Jason M.,
Ma Lijun,
Kelley David E.,
Pinto Shirly
Publication year - 2017
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.354
Subject(s) - diabetic nephropathy , medicine , renal function , endocrinology , fibrosis , nephropathy , podocyte , kidney , proteinuria , diabetes mellitus
Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK ‐0429, a compound that was originally developed as an α v β 3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK ‐0429 is an equipotent pan‐inhibitor of multiple av integrins. MK ‐0429 dose‐dependently inhibited podocyte motility and also suppressed TGF ‐ β ‐induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF 1 rat model of diabetic nephropathy, chronic treatment with MK ‐0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.