PGC1α/SIRT3-Mediated Oxidative Stress and Downregulation of NLRP3 Expression by Sodium Thiosulfate Pre- and Post-Treatment Accelerates Recovery from Ischemia–Reperfusion-Induced Acute Kidney Injury

Background: Renal ischemia–reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). It is associated with reduced blood flow as encountered in vascular surgery, including aortic aneurysm repair and kidney transplantation. In this study, we investigated whether pre- and/or post-administration of sodium thiosulfate (STS), an FDA-approved hydrogen sulfide donor drug, attenuated IRI-induced AKI in rats. Methods: AKI was induced in male rats by clamping both renal arteries for 60 min. At 30 min before clamping, and 30 min after reperfusion, STS was administered at a weigh-based dose to achieve a circulating concentration of 150 μM, after which the rats were kept in metabolic cages for urine and blood collection on postoperative days (POD) 3, 5, and 7. Rats were sacrificed on POD3, POD5, and POD7, and kidneys were harvested for analysis. Sham-operated rats received no treatment. Results: AKI was evidenced by markedly higher acute tubular necrosis score, and renal protein and gene expression of damage markers (KIM-1 and NGAL), as well as markers of oxidative stress (MDA, GSH, and SOD), inflammation (MPO, IL-6), and apoptosis (TUNEL). While significant incremental improvement was observed in the expression of these markers in the pre-treatment only and post-treatment only groups over the POD3–7 observation period compared to untreated control group (p < 0.05), superior renal protection was observed in the pre + post-treatment group (p < 0.01). Functionally, serum creatinine levels were significantly higher over the POD3–7 observation period in the untreated group relative to pre-treatment and post-treatment groups (p < 0.05), and markedly lower in the pre + post-treatment group (p < 0.001), which positively correlated with urine output. Urine osmolality was statistically similar to sham-operated rats on POD5 and 7, while all other groups showed decreased urine osmolality on POD3 and 5 (p < 0.05). Mechanistically, the protective effect of STS correlated with upregulation of PGC1α and SIRT3 protein and gene expression and downregulation of NLRP3 protein and mRNA expression in the pre + post-treatment group compared to other groups (p < 0.05). Conclusions: The present study reports for the first time the protective effect of STS against IRI-induced AKI, and indicates PGC1α, SIRT3, and NLRP3 as molecular targets of STS.