Reno-protective effect of nicorandil and pentoxifylline against potassium dichromate-induced acute renal injury via modulation p38MAPK/Nrf2/HO-1 and Notch1/TLR4/NF-κB signaling pathways.

Occupational and environmental exposure to chromium compounds such as potassium dichromate (PDC) (K2Cr2O7) has emerged as a potential aetiologic cause for renal disease through apoptotic, and inflammatory reactions. The known potent antioxidants such as nicorandil (NIC) and/or pentoxifylline (PTX) were studied for their possible nephroprotective effect in PDC-treated rats. Forty male Wistar rats were divided into five groups; control, PDC group, NIC+PDC, PTX+PDC group, and combination+PDC group. Nephrotoxicity was evaluated histopathologically and biochemically. Invasive blood pressure, renal function parameters urea, creatinine, uric acid and albumin, glomerular filtration rate markers Cys-C, Kim-1 and NGAL, inflammatory markers IL-1β, IL-6, TNF-α, TGF-β, COX-II, p38MAPK, NF-κB and TLR4, oxidative stress SOD, GSH, MDA, MPO, HO-1 and Nrf2 and apoptotic mediators Notch1 and PCNA were evaluated. Besides, renal cortical histopathology was assayed as well. PDC led to a considerable increase in indicators for kidney injury, renal function parameters, invasive blood pressure, oxidative stress, and inflammatory markers. They were markedly reduced by coadministration of PDC with either/or NIC and PTX. The NIC and PTX combination regimen showed a more significant improvement than either medication used alone. Our results demonstrated the nephroprotective effect of NIC, PTX, and their combined regimen on PDC-induced kidney injury through suppression of oxidative stress, apoptosis, and inflammatory response. Renal recovery from PDC injury was achieved through enhanced MAPK/Nrf2/HO-1 and suppressed Notch1/TLR4/NF-κB signaling pathways. This study highlights the role of NIC and PTX as effective interventions to ameliorate nephrotoxicity in patients undergoing PDC toxicity.

El-Shoura EAM ，Abdelzaher LA ，Ahmed AAN ，Abdel-Wahab BA ，Sharkawi SMZ ，Mohamed SA ，Salem EA ... -  《-》

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.

El-Shoura EAM ，Sharkawi SMZ ，Abdelzaher LA ，Abdel-Wahab BA ，Ahmed YH ，Abdel-Sattar AR ... -  《-》

Nicorandil combats doxorubicin-induced nephrotoxicity via amendment of TLR4/P38 MAPK/NFκ-B signaling pathway.

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks. Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 β), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination. Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B.

Khames A ，Khalaf MM ，Gad AM ，Abd El-Raouf OM ，Kandeil MA ... -  《-》

Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways.

Younis NS ，Elsewedy HS ，Shehata TM ，Mohamed ME ... -  《-》

Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs.

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.

Hassan NF ，El-Ansary MR ，Selim HMRM ，Ousman MS ，Khattab MS ，El-Ansary MRM ，Gad ES ，Moursi SMM ，Gohar A ，Gowifel AMH ... -  《-》