Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Abstract

Background/Aims: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. Methods: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. Results: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. Conclusion: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.

Candesartan and epigallocatechin‐3‐gallate ameliorate gentamicin‐induced renal damage in rats through p38‐MAPK and NF‐κB pathways

“…Numerous signaling pathways are involved in controlling apoptosis. Among them, NF‐κB p65 and p38‐MAPK are considered important intermediates for induction of apoptosis . NF‐κB represents a cornerstone of the inflammatory process during nephrotoxicity that is activated in response to ROS .…”

“…Among them, NF-κB p65 and p38-MAPK are considered important intermediates for induction of apoptosis. [49,50] NF-κB represents a cornerstone of the inflammatory process during nephrotoxicity that is activated in response to ROS. [13,51,52] A recent study indicated that the expression of NF-κB was upregulated in the kidney of rats administered gentamicin.…”

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

“…Research teams continue to investigate the nephrotoxic mechanisms of different widely used chemotherapy drugs, with hopes that in the future a panel of specific renal biomarkers can be used as the gold standard for early renal injury detection. Previous studies investigated the effect of the most frequent chemotherapy agents used in clinical practice on tubular renal cells and the effect on renal biomarkers [139,140,141,142,143,144,145,146,147] (Table 1).…”

The Effect of YiQiFuMai on Ischemic Heart Failure by Improve Myocardial Microcirculation and Increase eNOS and VEGF Expression

“…The activation of AKT leads to serine 1177 phosphorylation of eNOS, which can upregulate the expression of eNOS. In addition, activation of the PI3K/AKT/eNOS pathway can inhibit apoptosis in vascular endothelial cells [15]. AKT plays an important role in reducing cardiomyocyte apoptosis and myocardial protection.…”