Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration
Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration
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硫化氢上调肾 AQP-2 蛋白表达并促进尿液浓缩
DOI：
10.1096/fj.201800436r
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Li Chunling
中科院分区：
文献类型：
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作者：
Luo Renfei;Hu Shan;Liu Qiaojuan;Han Mengke;Wang Feifei;Qiu Miaojuan;Li Suchun;Li Xiaosa;Yang Tianxin;Fu Xiaodong;Wang Weidong;Li Chunling
越来越多的证据支持H2S在肾生理和肾损伤发病机制中的重要作用。H2S是否调节肾脏水代谢及其可能机制尚不清楚。本研究旨在确定H2S在尿液浓度中的作用。分别用炔丙基甘氨酸（PPG）和氨氧基乙酸（AOAA）抑制胱硫醚-γ-裂解酶（CSE）和胱硫醚-β-合成酶（CBS）（内源性H2S产生的2种主要酶），引起小鼠尿量增加和尿渗透压降低，这与肾内髓质水通道蛋白（AQP）-2表达降低有关。接受PPG和AOAA治疗的小鼠在脱水时出现尿浓度缺陷，伴有AQP-2蛋白表达降低。单独抑制CSE与杂合子CBS小鼠肾髓质中AQP-2蛋白水平的轻度降低相关。GYY 4137，一种缓慢的H2S供体，显著改善了锂诱导的肾源性尿崩症（NDI）小鼠的尿液浓度，并阻止了肾脏AQP-2蛋白表达的下调。GYY 4137显着增加由内髓集合管（IMCD）悬浮液制备的细胞裂解物中的cAMP水平。AQP-2蛋白表达也上调，但被腺苷酸环化酶抑制剂MDL 12330 A或PKA抑制剂H89显著抑制，而不是加压素2受体（V2 R）拮抗剂托伐普坦。抑制内源性H2S的产生损害了小鼠的尿液浓度，而外源性H2S供体通过增加集合管主细胞中AQP-2的表达来改善锂诱导的NDI中的尿液浓度。H2S上调AQP-2蛋白表达，可能通过cAMP-PKA途径。罗河，巴西-地Hu，S.，刘昆，汉，M.，王福，Qiu，M.，Li，S.，Li，X.，杨，T.，傅，X.，王伟，Li，C.硫化氢上调肾脏AQP-2蛋白表达并促进尿液浓缩。
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.