Pharmacologic Blockade of <i>α</i>v<i>β</i>1 Integrin Ameliorates Renal Failure and Fibrosis <i>In Vivo</i>.

Abstract

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells <i>in vivo</i> is poorly understood. PDGF receptor <i>β</i> (PDGFR<i>β</i>) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR<i>β</i> promoter-driven Cre system to delete <i>α</i>v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR<i>β</i>-Cre line to isolate and study renal fibroblasts <i>ex vivo</i> We found that renal fibroblasts express three <i>α</i>v integrins, namely <i>α</i>v<i>β</i>1, <i>α</i>v<i>β</i>3, and <i>α</i>v<i>β</i>5. Blockade of <i>α</i>v<i>β</i>1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-<i>β</i>1 and prevented activation of the latent TGF-<i>β</i> complex. Continuous administration of a recently described potent small molecule inhibitor of <i>α</i>v<i>β</i>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 <i>α</i>v<i>β</i>1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.