The potential protective role of L-citrulline against cadmium-induced renal dysfunction in male albino rats: The implications of the Nrf2/HO-1 antioxidant signaling pathway

Abstract

Cadmium (Cd), a prevalent ecological and occupational pollutant from industrial discharge that poses serious health hazards, is known to be harmful to the kidneys. L-citrulline (L-Cit), a non-essential amino acid that has shown potential in lowering oxidative stress and improving organ function, is a good candidate for achieving renal protection against Cd-induced impaired antioxidant defenses in albino rats. Four groups of thirty-two adult male albino rats each were randomly assigned: control, L-Cit, CdCl₂, and L-Cit + CdCl₂. The L-Cit + CdCl₂ group received 900 mg/kg L-Cit 120 min before Cd exposure, while the CdCl₂ group received 5 mg/kg Cd for 30 days. Biochemical assays evaluated kidney functions, oxidative stress markers, and quantitative RT-PCR gene expression analysis for nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Tissue damage and apoptosis were assessed using histopathological analyses and immunohistochemistry labeling for Nrf2, HO-1, and caspase-3. Exposure to Cd significantly increased blood creatinine, urea, and uric acid levels, suggesting impaired renal function. Concurrent delivery of L-Cit significantly ameliorated these changes, further improving markers of kidney function beyond those of the control groups. Furthermore, elevated MDA levels, decreased GSH content, reduced SOD and CAT activities, and decreased serum nitric oxide (NO) indicated oxidative stress due to Cd exposure. L-Cit treatment successfully lowered MDA levels and restored antioxidant enzyme abilities. Histopathological studies found that L-Cit administration significantly reduced the Cd-induced renal damage in rats. L-Cit also upregulates the HO-1 and Nrf2 expression, which report its protective antioxidant properties. The current study shows that L-Cit showed protective effects against Cd-induced nephrotoxicity by modulating the NO and Nrf2/HO-1 signaling pathways, offering promising therapeutic insights for managing heavy metal-induced renal damage. Its mechanics and therapeutic applications merit further investigation.