Isopropyl 3-(3,4-Dihydroxyphenyl)-2-Hydroxypropanoate Attenuates Experimental Renal Ischemia-Reperfusion Injury by Limiting Sterile Inflammation and Preserving Mitochondrial Function: Involvement of an Nrf2-Associated Cytoprotective Response.

Purpose: Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and a critical determinant of delayed graft dysfunction after kidney transplantation. Sterile inflammation, mitochondrial dysfunction, and oxidative stress are central drivers of renal IRI, yet effective pharmacologic interventions remain limited. Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP), an esterified derivative of Danshensu, has shown anti-inflammatory and antioxidant activity in other injury models, but its role in renal IRI remains unclear. Methods: A murine bilateral renal IRI model and a hypoxia/reoxygenation (H/R) model in HK-2 cells were used to evaluate the protective effects of IDHP. In the in vivo preventive treatment model, mice received IDHP at 15 mg/kg before ischemia and shortly after reperfusion. In vitro, HK-2 cells were pretreated with IDHP, and 10 μM was selected for subsequent experiments based on its protective efficacy and acceptable tolerability. Renal injury was assessed by serum creatinine (Scr), blood urea nitrogen (BUN), PAS staining, tubular injury scoring, and KIM-1 expression. Inflammation, mitochondrial function, oxidative stress, cytosolic mitochondrial DNA (mtDNA) release, and Nrf2-associated signaling were further examined. The involvement of Nrf2 was explored in HK-2 cells using the pharmacologic inhibitor ML385. Results: IDHP reduced Scr and BUN by 40.2% and 39.3%, respectively, compared with the IRI group, and alleviated histological features of tubular injury after renal IRI. IDHP also reduced macrophage and neutrophil accumulation, suppressed renal TNF-α, IL-6, and IL-1β expression, and increased IL-10 expression. IDHP preserved mitochondrial complex activity, restored ATP levels, reduced cytosolic mtDNA accumulation, attenuated oxidative stress, and enhanced Nrf2-associated antioxidant signaling in injured kidneys. In H/R-treated HK-2 cells, IDHP improved cell viability, reduced ROS accumulation, limited cytosolic mtDNA release, and decreased secretion of TNF-α, IL-6, MCP-1, and CXCL-8. In this in vitro model, ML385 partially blunted the protective effects of IDHP, suggesting that Nrf2-associated signaling may contribute to its cytoprotective actions. Conclusion: IDHP attenuates experimental renal IRI and H/R-induced tubular epithelial injury, potentially through coordinated suppression of sterile inflammation, preservation of mitochondrial function, reduction of oxidative stress, and engagement of Nrf2-associated cytoprotective signaling. These findings support further preclinical investigation of IDHP as a candidate renoprotective agent. However, dose-response, therapeutic window, long-term outcomes, and in vivo mechanistic studies remain necessary before clinical translation can be considered.