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

[摘要] 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 (PDGFR β ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR β promoter–driven Cre system to delete α 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 β -Cre line to isolate and study renal fibroblasts ex vivo . We found that renal fibroblasts express three α v integrins, namely α v β 1, α v β 3, and α v β 5. Blockade of α v β 1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF- β 1 and prevented activation of the latent TGF- β complex. Continuous administration of a recently described potent small molecule inhibitor of α v β 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 α v β 1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

[学科分类] 泌尿医学