Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Abstract

Renal damage is a devastating adverse effect for cyclosporine; a widely used immunosuppressant drug. The present work examined the potential of camel milk, a natural agent with marked anti-inflammatory/antioxidant properties, to attenuate cyclosporine-induced renal injury. The kidney tissue was examined with the aid of Western blotting, immunohistochemistry, biochemical assays, including colorimetric and ELISA kits. The present findings revealed that camel milk (10 mL/kg/day; for 3 weeks by gavage) significantly lowered serum creatinine, BUN, and KIM-1 renal dysfunction markers. Mechanistically, camel milk inhibited renal inflammation, as seen by significant decrease of the pro-inflammatory cytokines (MCP-1, TNF-α, IL-1β, and IL-18) and extracellular degradation signals (MMP-2 and MMP-9) and enhanced the generation of the anti-inflammatory IL-10. Moreover, it inhibited the upstream pro-inflammatory p38/ERK/JNK MAPK pathway by lowering the phosphorylation of the 3 subfamilies of MAPKs (p38 MAPK, JNK1/2, and ERK1/2). Furthermore, camel milk curbed the NF-κB pathway activation by downregulating the protein expression of activated NF-κBp65, p-NF-κBp65, and p-IκBα proteins. Additionally, camel milk inhibited renal oxidative stress by lowering the MPO activity and augmenting the reduced/oxidized glutathione ratio and total antioxidant capacity. These findings propose that camel milk may be a promising agent that inhibits cyclosporine-triggered renal inflammation via curtailing the p38/ERK/JNK MAPK and NF-κB pathways, matrix metalloproteinases, and pro-inflammatory cytokines.

Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease

“…One of the canonical MAPKs, p38, is classically upstream of NFκB. rhFSTL1 activates p38 in a time-dependent manner, and NFκB is downstream of ERK activation [39]. rhFSTL1 also activated NFκB-mediated gene expression in kidney tubular cells based on the activation of an NFκB promoter construct that also drove firefly luciferase expression.…”

The Antioxidant, Anti-Inflammatory and Immunomodulatory Effects of Camel Milk

“…Moreover, administration of CM (10 ml/kg/day of CM for 3 weeks) on cyclosporine-induced renal injury in male Wistar rats, markedly reduced the cancers, indicated by improving serum creatinine and blood urea nitrogen (BUN) levels, as well as kidney injury molecule-1 (KIM-1). As a result, CM decreased renal inflammation by the anti-inflammatory pathway of p38/extracellular signal-regulated kinases (ERK)/c, Jun N-terminal kinases (JNK) and mitogen-activated protein kinases (MAPK) ( 67 ).…”

“…Therefore, CM showed a protective effect against kidney toxicity by inhibiting ROS activity ( 66 ). Treatment with CM (10 ml/kg/day; for 3 weeks by gavage) in cyclosporine-induced kidney damage in male Wistar rats, reduced MPO activity but increased the reduced/oxidized ratio of GSH and TAC ( 67 ). Further, in albino white rats with cadmium chloride-induced toxicity, daily consumption of CM (2 ml of fresh CM for 21 days) increased SOD and CAT activities, indicating a protective effect of CM against the toxicity caused by cadmium chloride ( 104 ).…”

“…The effects of CM on reducing 5-FU-induced renal toxicity in rats, inhibited TNF-α and thus suppressed renal inflammation ( 66 ). The effects of CM on cyclosporine-induced kidney damage revealed that oral administration of CM (10 ml/kg/day for 3 weeks) caused a significant reduction in TNF-α, MCP-1, IL-1β and IL-18 ( 67 ).…”

Effects of Lycium barbarum glycopeptide on renal and testicular injury induced by di(2-ethylhexyl) phthalate

“…Mitogen-activated protein kinase (MAPK) signaling is relevant in cell differentiation, cell proliferation, and adaptation to environmental stress (Pearson et al 2001 ). p38 MAPK is a subgroup of MAPKs that can induce inflammation and fibrosis and lead to kidney damage (Zeng et al 2020 ; Arab et al 2021 ; Lindfors et al 2021 ; Qin et al 2021 ). Various stresses can cause body damage by inducing inflammation (Hussain et al 2016 ; Wirtz and von Känel 2017 ; Atrooz and Salim 2020 ).…”