Curnow Andrew C, Gonsalez Sabrina R, Gogulamudi Venkateswara R, Visniauskas Bruna, Simon Eric E, Gonzalez Alexis A, Majid Dewan S A, Lara Lucienne S, Prieto Minolfa C
Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Front Physiol. 2020 Nov 17;11:559341. doi: 10.3389/fphys.2020.559341. eCollection 2020.
In the kidney, the stimulation of renin production by the collecting duct (CD-renin) contributes to the development of hypertension. The CD is a major nephron segment for the synthesis of nitric oxide (NO), and low NO bioavailability in the renal medulla is associated with hypertension. However, it is unknown whether NO regulates renin production in the CD. To test the hypothesis that low intrarenal NO levels stimulate the production of CD-renin, we first examined renin expression in the distal nephron segments of CD-eNOS deficient mice. In these mice, specific CD-renin immunoreactivity was increased compared to wild-type littermates; however, juxtaglomerular (JG) renin was not altered. To further assess the intracellular mechanisms involved, we then treated M-1 cells with either 1 mM L-NAME (L-arginine analog), an inhibitor of NO synthase activity, or 1 mM NONOate, a NO donor. Both treatments increased intracellular renin protein levels in M-1 cells. However, only the inhibition of NOS with L-NAME stimulated renin synthesis and secretion as reflected by the increase in transcript and renin protein levels in the extracellular media, respectively. In addition, NONOate induced a fast mobilization of cGMP and intracellular renin accumulation. These response was partially prevented by guanylyl cyclase inhibition with ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1]. Accumulation of intracellular renin was blocked by protein kinase G (PKG) and protein kinase C (PKC) inhibitors. Our data indicate that low NO bioavailability increases CD-renin synthesis and secretion, which may contribute to the activation of intrarenal renin angiotensin system.
在肾脏中，集合管对肾素产生的刺激（集合管肾素）会导致高血压的发生。集合管是合成一氧化氮（NO）的主要肾单位节段，肾髓质中NO生物利用度低与高血压有关。然而，尚不清楚NO是否调节集合管中的肾素产生。为了验证肾内NO水平低会刺激集合管肾素产生这一假说，我们首先检测了CD-eNOS基因缺陷小鼠远端肾单位节段中的肾素表达。与野生型同窝小鼠相比，这些小鼠中特定的集合管肾素免疫反应性增加；然而，球旁（JG）肾素未发生改变。为了进一步评估其中涉及的细胞内机制，我们随后用1 mM L-NAME（L-精氨酸类似物，一种NO合酶活性抑制剂）或1 mM NONOate（一种NO供体）处理M-1细胞。两种处理均增加了M-1细胞内的肾素蛋白水平。然而，只有用L-NAME抑制NOS刺激了肾素的合成和分泌，分别表现为细胞外培养基中转录本和肾素蛋白水平的增加。此外，NONOate诱导了cGMP的快速动员和细胞内肾素的积累。用ODQ（1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1）抑制鸟苷酸环化酶可部分阻止这些反应。细胞内肾素的积累被蛋白激酶G（PKG）和蛋白激酶C（PKC）抑制剂阻断。我们的数据表明，低NO生物利用度会增加集合管肾素的合成和分泌，这可能有助于激活肾内肾素-血管紧张素系统。
