Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone
Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone
复制标题
DOI：
10.1038/s41440-023-01219-9
复制
发表时间：
2023-02
影响因子：
5.4
通讯作者：
Koji Ochiai;Y. Mochida;Takashi Nagase;H. Fukuhara;Yoshihiro Yamaguchi;M. Nagase
中科院分区：
文献类型：
--
作者：
Koji Ochiai;Y. Mochida;Takashi Nagase;H. Fukuhara;Yoshihiro Yamaguchi;M. Nagase
近年来，机械敏感性离子通道的发现促进了高血压和肾脏病领域的机械生物学研究。我们先前研究了Piezo 2在小鼠肾小球系膜和肾小球肾素生成细胞中的表达，以及脱水对其的调节。本研究旨在探讨Piezo 2在高血压肾病中的表达变化。还分析了非甾体盐皮质激素受体阻滞剂依沙西酮的作用。将4周龄的Dahl盐敏感大鼠随机分为3组：喂食0.3%NaCl饮食（DSN）的大鼠，喂食高8%NaCl饮食（DSH）的大鼠，以及喂食高盐饮食补充依萨昔酮（DSH + E）的大鼠。六周后，DSH大鼠出现高血压、蛋白尿、肾小球和血管损伤以及血管周围纤维化。依沙普利酮能有效降低血压，改善肾损害。Piezo 2在DSN大鼠肾小球系膜Pdgfrb阳性细胞和Ren 1阳性细胞中表达，在DSH大鼠肾小球系膜Piezo 2表达增强。此外，Piezo 2阳性细胞聚集在DSH大鼠肾内小动脉和小动脉的外膜层。这些细胞Pdgfrb、Col 1a 1和Col 3a 1阳性，而Acta 2（αSMA）阴性，表明它们是不同于肌纤维母细胞的血管周围间充质细胞。此外，Piezo 2抑制siRNA在培养的系膜细胞中导致Tgfb 1表达上调。在对照siRNA和Piezo 2siRNA的转染中，循环牵张也上调Tgfb 1。我们的研究结果表明，Piezo 2可能在调节高血压肾硬化的发病机制中起着重要作用，并强调了依沙昔酮对盐诱导的高血压肾病的治疗作用。已知机械通道Piezo 2在小鼠系膜细胞和肾小球肾素产生细胞中表达，这在血压正常的Dahl-S大鼠中得到证实。在盐诱导的高血压Dahl-S大鼠中，在肾小球系膜细胞、肾素细胞、尤其是血管周围间充质细胞中观察到Piezo 2上调，表明其参与肾脏纤维化。
The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reportedPiezo2expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate howPiezo2expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats,Piezo2was expressed inPdgfrb-positive mesangial andRen1-positive cells.Piezo2expression in these cells was enhanced in DSH rats. Moreover,Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive forPdgfrb,Col1a1, andCol3a1, but negative forActa2(αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts.Piezo2upregulation was reversed by esaxerenone treatment. Furthermore,Piezo2inhibition by siRNA in the cultured mesangial cells resulted in upregulation ofTgfb1expression. Cyclic stretch also upregulatedTgfb1in both transfections of control siRNA andPiezo2siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy.Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats,Piezo2upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis.