Abstract

TIRON ALLEVIATES CADMIUM-INDUCED RENAL AND TESTICULAR DAMAGE IN RATS: TARGETING NRF2/HO-1 AND AMPK/MTOR PATHWAYS

Doha M. Dagher, Marwa S. Zaghloul and Ghada M. Suddek*

ABSTRACT

Purpose: Cadmium (Cd) is a prevalent environmental pollutant that is known to have hazardous effects on human health, particularly testicular and renal impairment. Tiron, a water soluble synthetic analog of vitamin E, has long been recognized as a powerful antioxidant. The primary objective of the present study was to evaluate the possible protective effects of tiron against Cd-triggered renal and testicular damage in rats and the underlying mechanisms. Method: Cd (30 mg/kg) and tiron (100 and 200 mg/kg) were administered orally to rats for 21 days. Results: Tiron mitigated Cd-induced renal and testicular dysfunction as revealed by reduction in BUN, serum creatinine, and urinary total protein concentration concomitant with elevation in urinary creatinine, creatinine clearance, and serum testosterone. In addition, tiron effectively counteracted the histopathological alterations triggered by Cd. In parallel, tiron was capable of diminishing oxidative stress by decreasing MDA content, elevating GSH content and SODactivity. Additionally, tiron was capable of promoting the Nrf2/HO-1 signaling pathway. Tiron boosted the autophagy flux via modulation of the testicular and renal AMPK/mTOR pathway, which was proven by an elevation in the p-AMPK/total AMPK protein expression and a decrease in the p-mTOR/total mTOR protein expression. Furthermore, tiron attenuated caspase-3 expression, which contributed to the inhibition of apoptotic processes. Conclusion: Tiron successfully alleviated Cd-induced testicular and renal damage by mitigating oxidative stress and apoptosis and boosting autophagy flux. This was achieved through the augmentation of the Nrf2/HO-1 and modulation of AMPK/mTOR pathways.

Keywords: Tiron; Cadmium; autophagy; Nrf2; Kidney; testis.