title: Pharmacologic Blockade ofαvβ1 Integrin Ameliorates Renal Failure and FibrosisIn Vivo.
abstract: Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cellsin vivois poorly understood. PDGF receptorβ(PDGFRβ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRβpromoter-driven Cre system to deleteαv 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 fibroblastsex vivoWe found that renal fibroblasts express threeαv integrins, namelyαvβ1,αvβ3, andαvβ5. Blockade ofαvβ1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-β1 and prevented activation of the latent TGF-βcomplex. Continuous administration of a recently described potent small molecule inhibitor ofαvβ1, 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 ofαvβ1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California; cyongen@uci.edu.
authors.forename: Yongen
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California.
authors.forename: Wei Ling
authors.initials: WL
authors.lastname: Lau
authors.affiliation: Department of Pharmaceutical Chemistry and.
authors.forename: Hyunil
authors.initials: H
authors.lastname: Jo
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, California; and.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsujino
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee.
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, California; and.
authors.forename: Nilgun Isik
authors.initials: NI
authors.lastname: Reed
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, California; and.
authors.forename: Amha
authors.initials: A
authors.lastname: Atakilit
authors.affiliation: Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California.
authors.forename: Ane Claudia Fernandes
authors.initials: ACF
authors.lastname: Nunes
authors.affiliation: Department of Pharmaceutical Chemistry and.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, California; and.
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000502:physiology; D051437:Renal Insufficiency / Q000209:etiology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D006146:Guanidines; D019030:Receptors, Vitronectin; D013449:Sulfonamides; C094340:integrin alphavbeta1
keywords: Adenine; CKD; Integrin; TGFβ; UUO; renal fibrosis