A dual αvβ1/αvβ6 integrin inhibitor Bexotegrast (PLN-74809) ameliorates organ injury and fibrogenesis in fibrotic kidney disease

Abstract

Chronic kidney disease (CKD) is a global public health problem, involving about 10% of the global population. Unfortunately, there are currently no effective drugs. Kidney fibrosis is the main pathology of CKD, where integrins play crucial roles in renal fibrogenesis. Recently, Bexotegrast (PLN-74809) as a dual integrin αvβ1/αvβ6 inhibitor could reduce the degree of lung fibrosis in patients with idiopathic pulmonary fibrosis. However, the role of PLN-74809 remains unclear in fibrotic kidney disease. Here, we have revealed that PLN-74809 administration dose-dependently delayed the progression of renal fibrosis in both adenine diet- and unilateral ureteral obstruction (UUO)-induced mice. Mechanistically, PLN-74809 targeted integrin αvβ1/αvβ6 to inhibit FAK/Src/Akt/β-catenin cascade in fibrotic kidneys. In summary, our results for the first time highlighted the αvβ1/αvβ6 inhibitor PLN-74809 exerted potential therapeutic against kidney fibrosis.