Sedaka Randee, Hyndman Kelly A, Mironova Elena, Stockand James D, Pollock Jennifer S
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F297-F307. doi: 10.1152/ajprenal.00323.2020. Epub 2020 Dec 28.
We reported that high salt (HS) intake stimulates renal collecting duct (CD) endothelin (ET) type B receptor (ETR)/nitric oxide (NO) synthase 1β (NOS1β)-dependent NO production inhibiting the epithelial sodium channel (ENaC) promoting natriuresis. However, the mechanism underlying the HS-induced increase of NO production is unclear. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. The renal inner medulla (IM), in particular the IMCD, has the highest NOS1 activity within the kidney. Hence, we hypothesized that HS intake provokes HDAC1 activation of NO production in the IM. HS intake for 1 wk significantly increased HDAC1 abundance in the IM. Ex vivo treatment of dissociated IM from HS-fed mice with a selective HDAC1 inhibitor (MS-275) decreased NO production with no change in ET-1 peptide or mRNA levels. We further investigated the role of the ET-1/ETR/NOS1β signaling pathway with chronic ETR blockade (A-192621). Although NO was decreased and ET-1 levels were elevated in the dissociated IM from HS-fed mice treated with A-192621, ex vivo MS-275 did not further change NO or ET-1 levels suggesting that HDAC1-mediated NO production is regulated at the level or downstream of ETR activation. In split-open CDs from HS-fed mice, patch clamp analysis revealed significantly higher ENaC activity after MS-275 pretreatment, which was abrogated by an exogenous NO donor. Moreover, flow-induced increases in mIMCD-3 cell NO production were blunted by HDAC1 or calcium inhibition. Taken together, these findings indicate that HS intake induces HDAC1-dependent activation of the ETR/NO pathway contributing to the natriuretic response.
我们曾报道，高盐（HS）摄入会刺激肾集合管（CD）内皮素（ET）B型受体（ETR）/一氧化氮（NO）合酶1β（NOS1β）依赖性NO生成，抑制上皮钠通道（ENaC），促进尿钠排泄。然而，HS诱导NO生成增加的潜在机制尚不清楚。组蛋白去乙酰化酶1（HDAC1）会对液体流量增加作出反应，HS摄入期间CD中就可能出现这种情况。肾内髓质（IM），尤其是内髓集合管（IMCD），在肾脏中具有最高的NOS1活性。因此，我们推测HS摄入会引发HDAC1激活IM中的NO生成。HS摄入1周会显著增加IM中HDAC1的丰度。用选择性HDAC1抑制剂（MS-275）对HS喂养小鼠分离的IM进行离体处理，可降低NO生成，而ET-1肽或mRNA水平无变化。我们进一步研究了慢性ETR阻断（A-192621）时ET-1/ETR/NOS1β信号通路的作用。尽管在用A-192621处理的HS喂养小鼠分离的IM中NO减少而ET-1水平升高，但离体MS-275并未进一步改变NO或ET-1水平，这表明HDAC1介导的NO生成在ETR激活水平或下游受到调节。在HS喂养小鼠的劈开的CD中，膜片钳分析显示MS-275预处理后ENaC活性显著更高，而外源性NO供体可消除这种活性。此外，HDAC1或钙抑制可减弱流体诱导的mIMCD-3细胞NO生成增加。综上所述，这些发现表明HS摄入会诱导HDAC1依赖性激活ETR/NO途径，从而导致尿钠排泄反应。
