Increasing evidence supports the important role of H₂S in renal physiology and the pathogenesis of kidney injury. Whether H₂S regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of H₂S in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), 2 major enzymes for endogenous H₂S production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow H₂S donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (V₂R) antagonist tolvaptan. Inhibition of endogenous H₂S production impaired urine concentration in mice, whereas an exogenous H₂S donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. H₂S upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

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