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Perindopril Dampens Cd-induced Nephrotoxicity by Suppressing Inflammatory Burden, Ang II/Ang 1–7, and Apoptosis Signaling Pathways

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Abstract

Cadmium (Cd) is one of the most abundant toxic heavy metals, and its exposure is linked to serious kidney intoxication, a major health problem. Evidence reported that inflammatory damage is a key factor in Cd renal intoxication. Perindopril (PER) is an angiotensin-converting enzyme inhibitor approved for treating hypertension and other cardiovascular problems. Significantly, RAS activation results in inflammatory damage. Our study aimed to examine the renoprotective effects of PER in Cd-induced nephrotoxicity, the impact of inflammation, and the underlying molecular mechanisms. PER was given at a dose of 1 mg/kg per day. Cd was injected at a dose of 1.2 mg/kg, as a single dose. Treatment with PER led to a significant decrease in serum levels of urea, creatinine, uric acid, and urine albumin/creatinine ratio. PER effectively mitigated inflammation by decreasing MPO, NO, IL-1β, IL-6, and INF-γ levels mediated by downregulating NF-κB expression and suppressing JAK-1 and STAT3 phosphorylation. PER modulates Ang II/Ang 1-7 axis in Cd-intoxicated rats by decreasing Ang II expression and increasing Ang-(1-7) expression. PER inhibits Cd-induced apoptosis by lowering Bax, cytochrome c, and cleaved caspase 3 expressions while increasing Bcl-2 expression. In conclusion, PER dampens Cd-induced kidney intoxication by modulating Ang II/Ang 1-7 axis, suppressing NF-κB, JAK-1/STAT3, and apoptosis signals.

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Authors and Affiliations

  1. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Kingdom of Saudi Arabia

    Zuhair M. Mohammedsaleh

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt

    Emad H. M. Hassanein & Fares E. M. Ali

  3. Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia

    Hanan S. Althagafy

  4. Department of Biology, Jamoum University College, Umm Al-Qura University, 21955, Makkah, Saudi Arabia

    Nouf S. Al-Abbas

  5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt

    Ahmed M. Atwa

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  1. Zuhair M. Mohammedsaleh
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Contributions

ZMM: statistical analysis, resources, reviewing, and editing. EH: conceptualization, data curation, writing-original draft preparation, formal analysis. FA: conceptualization, methodology, statistical analysis, data curation, reviewing, and editing. HSA: conceptualization, resources, reviewing, and editing. NSA: resources, data curation, reviewing, and editing. AMA: conceptualization, methodology, writing—original draft preparation, reviewing, and editing.

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Correspondence to Fares E. M. Ali.

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This experimental procedure was carried out following the approval of the Faculty of Pharmacy Ethics Committee of Al-Azhar University, Assiut Branch, Egypt (Approval number: ZA-AS/PH/17/C/2022).

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Mohammedsaleh, Z.M., Hassanein, E.H.M., Ali, F.E.M. et al. Perindopril Dampens Cd-induced Nephrotoxicity by Suppressing Inflammatory Burden, Ang II/Ang 1–7, and Apoptosis Signaling Pathways. Biol Trace Elem Res 202, 3193–3203 (2024). https://doi.org/10.1007/s12011-023-03907-6

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