Empagliflozin Mitigates TMAO-Induced NLRP3 Inflammation and Alters Transporter Expression in Renal Proximal Tubular Cells
Abstract
The gut-microbe-derived metabolite, trimethylamine N-oxide (TMAO), not only exhibits elevated levels but also serves as a predictor of higher mortality in patients with chronic kidney disease (CKD). In additional to CKD, elevated TMAO levels were also observed in organic anion transporter 3 (OAT 3) knockout mice and in the presence of trimethoprim, an antibiotic known for inhibiting multiple transporters on renal proximal tubule (PT) cells. These findings suggest that plasma TMAO level is a marker for diminished transporter function in PT cells. Moreover, the pro-inflammatory effects of TMAO on PT cells is relatively underexplored. Besides reno-protective effect, a recent study has shown that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates hyperuricemia by enhancing efflux transporter function. Therefore, we propose that empagliflozin can ameliorate TMAO-induced inflammation in PT cells by regulating the expression of membrane transporters. Western blotting results revealed that empagliflozin mitigated TMAO-induced NLRP3 inflammatory cytokines IL-1β, and IL-18. Additionally, empagliflozin reduced the elevated serum levels of TMAO in a CKD mouse model resulting from 5/6 nephrectomy (5/6Nx). Immuno-fluorescent staining demonstrated that TMAO decreased the expression of the basolateral transporter organic anion transporter 1 (OAT1) but increased the expression of apical membrane transporters ATP-binding cassette super-family G member 2 (ABCG2) on…
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