S14G-humanin attenuates renal ischaemia-reperfusion injury, potentially through activation of STAT3 and ERK1/2 signalling pathways in rats.

Renal ischaemia-reperfusion (I/R) injury leads to acute tubular necrosis and renal failure, triggering pathological mechanisms including inflammation, reactive oxygen species generation, apoptosis and mitochondrial dysfunction. The mitochondrial peptide humanin (HN), known to possess anti-apoptotic and anti-inflammatory properties, has been shown to counteract oxidative stress and restore mitochondrial function. This study aimed to investigate the effects of S14G-humanin (humanin G, HNG) on renal I/R injury. Sprague-Dawley male rats were divided into four groups (n = 48): (1) Sham, (2) I/R, (3) HNG-Sham, and (4) HNG-I/R. In I/R groups, renal artery ligation was performed for 45 min followed by 24-h reperfusion. HNG (2 mg/kg, i.v.) was administered 10 min before reperfusion. Urine was collected during reperfusion, and the experiment was terminated by collecting blood and tissue samples. Blood urea nitrogen and serum creatinine levels were elevated in the I/R group and were not affected by HNG treatment. Glutathione level and superoxide dismutase activity, which were diminished in the I/R group, were significantly restored following HNG administration. Myeloperoxidase activity and malondialdehyde levels were significantly decreased in HNG-I/R group compared to the I/R group. ATP levels and mitochondrial complex I activity were significantly increased in the HNG-I/R group compared to I/R. The percentage of apoptotic cells, markedly increased in I/R, was significantly reduced in HNG-I/R. Signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation also increased in HNG-I/R rats compared to I/R animals. HNG mitigates renal I/R injury by attenuating oxidative stress, inflammation and apoptosis while enhancing antioxidant capacity and mitochondrial function, through STAT3 and/or ERK1/2 activation.