Lactoferrin alleviates cyclophosphamide induced-nephropathy through suppressing the orchestration between Wnt4/β-catenin and ERK1/2/NF-κB signaling and modulating klotho and Nrf2/HO-1 pathway

Cyclophosphamide is an alkylating agent with vast arrays of therapeutic activity. Currently, its medical use is limited due to its numerous adverse events, including nephrotoxicity. This study aimed to follow the molecular mechanisms behind the potential renoprotective action of lactoferrin (LF) against cyclophosphamide (CP)-induced renal injury. For fulfillment of our aim, Spragw-Dwaly rats were orally administrated LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). Treatment of CP-injured rats with LF significantly reduced the elevated creatinine and blood urea nitrogen (BUN), markedly upregulated Nrf2/HO-1 signaling with consequent increase in renal total antioxidant capacity (TAC) and decrease in renal malondialdehyde (MDA) level. Furthermore, LF treatment significantly reduced the elevated renal p-ERK1/2 expression, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB) levels in CP-treated animals. Interestingly, LF treatment downregulated Wnt4/β-catenin signaling and increased both renal klotho gene expression and serum klotho level. Furthermore, LF treatment reduced apoptosis in kidney tissue via suppressing GSK-3β expression and modulating caspase-3 and Bcl2 levels. Histopathological examination of kidney tissue confirmed the protective effect of LF against CP-induced renal injury. The present findings document the renoprotective effect of LF against CP-induced nephropathy, which may be mediated via suppressing ERK1/2/ NF-κB and Wnt4/β-catenin trajectories and enhancing klotho expression and Nrf2/HO-1 signaling. Schematic graph for the protective mechanisms of lactoferrin against cyclophosphamide-induced kidney injury. APC: Adenomatosis polyposis coli; Bcl-2: B-cell lymphoma; DVL: Dishevelled; ERK1/2: extracellular signal-regulated kinases 1 and 2; GSK-3β; glycogen synthase kinase-3 beta; IL-6: interleukin 6; LF: Lactoferrin; LRP-5/6: Lipoprotein receptor-related protein; Nrf2: nuclear factor erythroid 2-related factor 2; NF-κB: nuclear factor-kappa B; ROS: reactive oxygen species; TNF-α: tumor necrosis factor –α.; Wnt4: wingless-related integration site 4. [Display omitted]