Ellagitanins are natural and complex polyphenolic compounds enriched in foods and commercial supplements. They are initially hydrolyzed to ellagic acid and further metabolized to urolithins by the gut microbiome. Ellagitanins are among a number of endogenous compounds found in fruits, nuts and vegetables that comprise a cardio protective diet for humans; however, biotransformation to urolithins may underlie their protective effects. Chronic treatment with urolithin A conveys anti-fibrotic and anti-inflammatory actions in experimental models of brain, cardiac, and kidney injury. Since the cellular actions and signaling events of urolithin A are undefined in renal cells, we assessed the influence of urolithin A on the TGF-β-PAI-1 pathway in NRK-52e cells, a well-characterized model of the proximal tubule epithelium and TGF-β induced signaling. TGF-β stimulated PAI-1 release 12-fold which was abolished by both urolithin A and the TGF-β receptor kinase inhibitor SB525334. The PAI-1 response to TGF-β was also blocked by the EGF receptor (EGFR) kinase inhibitors AG1478 and lapatinib implicating EGFR transactivation by TGF-β to evoke PAI-1 release in the renal cells. Indeed, EGF directly stimulated PAI-1 release that was abolished by urolithin A as well as the EGFR inhibitors. Moreover, both urolithin A and AG1478 blocked EGFR auto phosphorylation induced by EGF. The present studies suggest that the microbiome product urolithin A abrogates the stimulated release of PAI-1 by blocking the phosphorylation (activation) of the EGFR in NRK-52e renal epithelial cells.
Published Date: 2020-02-21; Received Date: 2020-01-31