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J Am Soc Nephrol. 2017 Jul;28(7):1998-2005. doi: 10.1681/ASN.2015050585. Epub 2017 Feb 20.

Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Author information

1
Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California; cyongen@uci.edu.
2
Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California.
3
Department of Pharmaceutical Chemistry and.
4
Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, California; and.
5
Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee.

Abstract

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 β (PDGFRβ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRβ promoter-driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRβ-Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three αv integrins, namely αvβ1, αvβ3, and αvβ5. Blockade of αvβ1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-β1 and prevented activation of the latent TGF-β complex. Continuous administration of a recently described potent small molecule inhibitor of αvβ1, 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 αvβ1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

KEYWORDS:

Adenine; CKD; Integrin; TGFβ; UUO; renal fibrosis

PMID:
28220032
PMCID:
PMC5491273
DOI:
10.1681/ASN.2015050585
[Indexed for MEDLINE]
Free PMC Article

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