Role of Nrf2/HO-1 and cytoglobin signaling in the protective effect of indole-3-acetic acid and chenodeoxycholic acid against kidney injury induced by valproate.

Background: Purpose: Valproate (VPA) is an antiepileptic drug widely used to treat various psychiatric and neurological disorders. Although its use is generally considered safe, chronic administration may lead to kidney injury. The mechanisms underlying VPA kidney toxicity are not entirely explored. This has prompted our investigation into a novel molecular signaling pathway involved in VPA-induced kidney injury and the exploration of strategies to ameliorate this toxicity using indole-3-acetic acid (IAA) and chenodeoxycholic acid (CDCA).

Methods: Rats were divided as follows: group I (control); group II (VPA group), where rats were administered VPA (500 mg/kg, i.p.) daily to induce kidney injury for 3 weeks; and groups III and IV, where rats were orally treated with either IAA (40 mg/kg) or CDCA (90 mg/kg), respectively, 1h post-VPA dose, for 3 weeks. The effects of these compounds on kidney tissues were evaluated with a focus on their antioxidant and anti-inflammatory properties using biochemical, histopathological, and immunohistochemical analyses.

Results: VPA caused a significant reduction in renal glutathione (GSH) and heme oxygenase-1 (HO-1) levels, and superoxide dismutase (SOD) activity, along with a significant elevation in malondialdehyde (MDA) levels. Similarly, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) levels were significantly increased. Immunohistochemical analysis demonstrated a significant decline in the immunoreactivity of nuclear factor erythroid 2-related factor (Nrf2) and cytoglobin antigens in renal cells. However, administration of either IAA or CDCA significantly ameliorated these altered parameters, including Nrf2/HO-1 and cytoglobin levels.

Conclusion: IAA and CDCA alleviated the kidney injury induced by VPA via downregulating the inflammatory response and upregulating the antioxidant capacity in renal tissue.