Pharmacologic Blockade of α v β 1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo

• Published in: Journal of the American Society of Nephrology 2017-07, Vol.28 (7), p.1998
• Main Authors: Chang, Yongen, Lau, Wei Ling, Jo, Hyunil, Tsujino, Kazuyuki, Gewin, Leslie, Reed, Nilgun Isik, Atakilit, Amha, Nunes, Ane Claudia Fernandes, DeGrado, William F, Sheppard, Dean
• Format: Article
• Language: English
• Subjects: Animals; Fibrosis - etiology; Fibrosis - prevention & control; Guanidines - pharmacology; Guanidines - therapeutic use; Kidney - pathology; Male; Mice; Receptors, Vitronectin - antagonists & inhibitors; Receptors, Vitronectin - physiology; Renal Insufficiency - etiology; Renal Insufficiency - prevention & control; Sulfonamides - pharmacology; Sulfonamides - therapeutic use
• ISSN: 1533-3450
• DOI: 10.1681/ASN.2015050585

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