Investigation of the Renal Defensive Influence of Walnut Septa Extract Against Acute Renal Ischemia/Reperfusion Injury

<b>Aim:</b> Acute kidney injury (AKI), also known as renal failure among the public, is the sudden decrease or loss of kidney functions. In the treatment of this condition, drugs with anti-inflammatory properties are generally preferred, but these drugs have many side effects. Physicians may need natural antioxidants as an alternative or additional treatment to the applied treatment to eliminate or reduce these side effects. Therefore, we conducted our current study molecularly to reveal the protective potential of walnut septa extract (WSE) in targeting oxidative stress, inflammation, ferroptosis, and cellular differentiation mechanisms in kidney tissues in Sprague-Dawley rats with kidney damage. <b>Methods:</b> The bioactive compounds in this extract were identified. Before inducing a renal IR injury model in the rats this extract was administered. Then, tissue oxidative stress markers were detected by ELISA. Following the treatment, molecular analyses were performed to determine antioxidant, anti-inflammatory, ferroptosis, and cellular differentiation activities in kidney tissues. Gene expression levels of kidney injury molecule-1 (<i>Kim-1</i>), nuclear factor erythroid 2 (<i>Nrf2</i>), lipocalin 2 (<i>Lcn2</i>), glutathione (GSH) peroxidase 4 (<i>Gpx4</i>), and keratin 8 (<i>Krt8</i>) were assessed. <b>Results:</b> The primary bioactive compound identified in this extract was β-sitosterol, accounting for 62.066% of the total extract. Pretreatment with WSE led to an increase in GSH activity and a reduction in lactate dehydrogenase (LDH) levels in the kidney tissues. On a molecular level, this extract promoted the activation of <i>Gpx4</i>, <i>Krt8</i>, and <i>Nrf2</i> genes, while inhibiting the expression of <i>Kim-1</i> and <i>Lcn2</i> genes, indicating its protective effects. Extract was shown to exert renoprotective effects by reducing oxidative stress (<i>Gpx4</i> and <i>Nrf2</i>), suppressing inflammation (<i>Lcn2</i> and <i>Kim-1</i>), and supporting cellular structure and apoptosis regulation (<i>Krt8</i>). <b>Conclusion:</b> These findings suggest that extract could be a promising therapeutic candidate for renal ischemia-reperfusion (RIR) injury. Further comprehensive and long-term studies are recommended to validate these findings.