Synergistic protective activity of sodium hydrosulfide and L-arginine against cisplatin-induced nephrotoxicity, even during nitric oxide synthase inhibition

Khurshid, Faria, Iqbal, Javeid, Ahmad, Fiaz-ud-Din, Javaid, Sana, Kanwal, Almas, Malik, Abdul, Akhtar, Suhail, Bux, Marvi Imam, Ahmad, Zainab, Siddiqui, Nikhat J. and Sewell, Robert D.E. 2025. Synergistic protective activity of sodium hydrosulfide and L-arginine against cisplatin-induced nephrotoxicity, even during nitric oxide synthase inhibition. The Journal of Pharmacology and Experimental Therapeutics 392 (7) , 103618. 10.1016/j.jpet.2025.103618

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Abstract

Cisplatin is a chemotherapeutic drug that induces nephrotoxicity through inflammation and oxidative stress. Hydrogen sulfide (H2S) and nitric oxide (NO) are gaseous signaling molecules with cytoprotective potential in renal damage. The current study evaluated the nephroprotective potential of sodium hydrosulfide (NaHS), an H2S donor, and L-arginine, a NO precursor, against cisplatin-induced nephrotoxicity, even under NO synthase inhibition. Wistar rats were treated with cisplatin (5 mg/kg) to induce nephrotoxicity while administered with L-NG-nitro-L-arginine methyl (L-NAME), NaHS, and L-arginine either alone or in combination for 28 days. Renal function was assessed by monitoring various parameters, including body weight and urinary flow. Moreover, H2S, NO, creatinine level and clearance, blood urea nitrogen (BUN), electrolyte levels, and oxidative stress were monitored in body fluids. The findings revealed that L-NAME exacerbated cisplatin-induced nephrotoxicity, which was evident from reduced weights (P < .0001) and elevated urine output (P < .01), H2S (P < .0001), NO (P < .0001), creatinine (P < .01), and BUN (P < .0001) levels, along with reduced sodium and potassium (P < .0001) and elevated oxidative stress markers (P < .001) in plasma compared with healthy rats. The treatment with NaHS and L-arginine markedly protected against L-NAME + cisplatin-induced nephrotoxicity as the parameters were reinstated, including urine output (P < .01), H2S (P < .01), NO (P < .0001), creatinine (P < .05), and BUN (P < .01) levels compared with L-NAME + cisplatin rats. Moreover, coadministration of NaHS + L-arginine restored the sodium (P < .0001) and potassium (P < .01) levels in plasma and mitigated oxidative stress (P < .05). The results suggested that H2S and NO mitigated L-NAME + cisplatin-induced nephrotoxicity by ameliorating the L-NAME + cisplatin-induced oxidative stress.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy
Publisher:	American Society for Pharmacology and Experimental Therapeutics (ASPET)
ISSN:	0022-3565
Date of Acceptance:	21 May 2025
Last Modified:	26 Aug 2025 15:30
URI:	https://orca.cardiff.ac.uk/id/eprint/180671

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