Ertugliflozin ameliorates thioacetamide-induced renal injury by modulating Nrf2-mediated oxidative stress, TLR4/STAT3 inflammatory signaling, and YAP/TAZ fibrotic pathways.

Kidney damage, often caused by oxidative stress and inflammation, can lead to renal failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including Ertugliflozin (Ertu), demonstrate renoprotective effects that may extend beyond glucose control. Our research studied the therapeutic potential and underlying mechanisms of Ertu against subchronic kidney injury in rats induced by TAA, focusing on the integrative crosstalk between oxidative stress, TLR4/STAT3 inflammation, and the YAP/TAZ fibrotic pathway, a previously unexplored axis for SGLT2 inhibitors in nephroprotection. Rats were divided into four groups: control, TAA-induced renal damage, and TAA-induced damage treated with Ertu (5 or 10 mg/kg). We assessed renal function (creatinine, urea), oxidative stress (GSH, MDA, Nrf2), inflammation (IL-1β, TNF-α, TLR4, STAT3/p-STAT3), and fibrosis (YAP1, TAZ, TGF-β1) in serum and renal tissue. Immunohistochemistry was performed to quantify TLR4 and Caspase-1 expression. TAA administration significantly induced renal dysfunction, oxidative stress, and inflammation, evidenced by elevated creatinine, urea, MDA, IL-1β, TNF-α, TLR4, and p-STAT3/STAT3 ratio, alongside depleted GSH and Nrf2. Fibrotic markers (YAP1, TAZ, TGF-β1) were also markedly upregulated. Ertu treatment, particularly at the 10 mg/kg dose, effectively reversed these alterations. It restored antioxidant defenses (GSH, Nrf2), suppressed inflammatory signaling (TLR4/IL-1β/TNF-α), normalized STAT3 activation, and downregulated profibrotic pathways. Histological improvements corroborated these biochemical findings. Ertugliflozin confers significant protection against renal damage caused by TAA by concurrently modulating oxidative stress, inflammation, and fibrotic signaling. These mechanistic findings underscore its potential as a repurposed therapeutic agent for subchronic kidney injury.