The angiotensin II receptor antagonist telmisartan promotes renal recovery after ischemia-reperfusion injury by reprogramming fatty acid metabolism

Current clinical guidelines recommend withholding renin-angiotensin-aldosterone system (RAAS) inhibitors during acute kidney injury (AKI) due to concerns over impaired glomerular perfusion. However, their potential to mitigate post-AKI inflammation and fibrosis remains unexplored. We hypothesized that telmisartan, an angiotensin II receptor blocker (ARB) with reported peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, would enhance recovery from ischemic AKI. Male Wistar rats were subjected to unilateral nephrectomy and 45-min ischemia in the contralateral kidney, or sham surgery. Animals were randomized to receive telmisartan (3 mg/kg/day) or placebo for 10 days, starting 1 wk before injury. Telmisartan treatment significantly accelerated the recovery of renal function and attenuated tubular necrosis, inflammation, and the expression of injury biomarkers. At the whole kidney tissue level at 72 h postischemia-reperfusion injury (IRI), bulk RNA-sequencing compared with healthy control mice without IRI revealed apparent broad metabolic dysfunction, with suppression of fatty acid oxidation and mitochondrial pathways, which may reflect both injury-driven changes in cellular composition and transcriptional regulation within surviving cells. These transcriptomic findings 72 h after IRI were significantly blunted or even abolished by telmisartan. These treatment effects did not show evidence of direct PPAR-γ pathway activation. This study suggests that the metabolic modulatory effects of certain angiotensin II receptor blockers may provide therapeutic benefit during the recovery phase of AKI, independent of direct PPAR-γ signaling.<b>NEW & NOTEWORTHY</b> RAAS inhibitors are routinely withheld during acute kidney injury (AKI) because of concerns about impaired renal perfusion. Contrary to this dogma, we show that telmisartan enhances renal recovery following ischemia-reperfusion injury. Transcriptomic analyses reveal that telmisartan restores fatty acid oxidation and mitochondrial-peroxisomal lipid metabolism, key pathways suppressed in AKI. These findings suggest that selected RAAS inhibitors may actively promote post-AKI metabolic recovery rather than merely pose hemodynamic risk.