Renoprotective Effect of S14G-Humanin on Renal Ischemia/Reperfusion Injury by Activation of STAT3 and ERK 1/2 Signal Transduction Pathways in Rats

Renal ischemia/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 HN on renal I/R injury. Sprague-Dawley male rats were divided into four groups (n = 48): 1.Sham, 2.I/R, 3.HN-Sham, 4.HN-I/R. In I/R groups, renal artery ligation was performed for 45 minutes followed by 24-hour reperfusion. Humanin G (HNG) (2 mg/kg, iv) was administered 10 minutes 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 levels as well as superoxide dismutase activities, which were diminished in the I/R group, were significantly restored following HNG administration. Myeloperoxidase activity and malondialdehyde levels were significantly decreased in HN-I/R group compared to the I/R group. ATP levels and mitochondrial Complex I activity were significantly increased in the HN-I/R group compared to I/R. The percentage of apoptotic cells, markedly increased in I/R, was significantly reduced in HN-I/R. STAT3 and ERK 1/2 phosphorylation also increased in HN-I/R rats compared to I/R animals. HNG exerts a protective effect against renal I/R injury by attenuating oxidative stress, inflammation, and apoptosis while enhancing antioxidant capacity and mitochondrial function, through STAT3 and/or ERK 1/2 activation.