Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 28, Issue 7, Pages 1998-2005Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2015050585
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Funding
- Ben J. Lipps Research Fellowship from the American Society of Nephrology (ASN)
- National Institute of Diabetes and Digestive and Kidney Diseases [F32DK100084]
- National Heart, Lung, and Blood Institute [HL123423]
- University of California, San Francisco Program in Biomedical Breakthrough by the Sandler Foundation
- Division of Nephrology and Hypertension at University of California, Irvine
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Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor beta (PDGFR beta) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRb promoter-driven Cre system to delete av integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRb-Cre line to isolate and study renal fibroblasts ex vivo. We found that renal fibroblasts express three av integrins, namely alpha v beta 1, alpha v beta 3, and alpha v beta 5. Blockade of alpha v beta 1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-beta 1 and prevented activation of the latent TGF-beta complex. Continuous administration of a recently described potent small molecule inhibitor of alpha v beta 1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of alpha v beta 1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
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