Activation of Piezo1 downregulates renin in juxtaglomerular cells and contributes to blood pressure homeostasis

Abstract

Background The synthesis and secretion of renin in juxtaglomerular (JG) cells are closely regulated by the blood pressure. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear. Results Here we discovered that Piezo1, a mechanosensitive ion channel, was colocalized with renin in mouse kidney as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and downregulated the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, mechanical stress using microfluidics also induced an intracellular calcium increase in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule PGE2 in JG cells. Surprisingly, we discovered that increased PGE2 could decreased the renin expression through the PGE2 receptor EP1 and EP3, which inhibited the cAMP production in JG cells. In mice, we found that activation of Piezo1 significantly downregulated the renin expression and blood pressure in wildtype but not adeno-associated virus (AAV)-mediated kidney specific Piezo1 knockdown mice. Conclusions In summary, these results revealed that activation of Piezo1 could downregulate the renin expression in JG cells and mice, subsequently a reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system.

PIEZO Ion Channels in Cardiovascular Functions and Diseases

“…Further in vivo studies in mice indicated that activation of PIEZO1 by Yoda1 downregulates renin expression and decreases the mean BP level, while adeno-associated virus-mediated PIEZO1 knockdown in the kidney abrogates the effects of Yoda1. 115 Together, these results revealed that the activation of PIEZO1 in juxtaglomerular cells decreases renin expression and regulates BP, highlighting its therapeutic potential as a drug target of the renin-angiotensin system. At variance, Mochida et al 117 found that PIEZO2 was expressed in glomerular mesangial cells and renin-producing juxtaglomerular cells at both the mRNA and protein levels.…”

“…Recent Yang et al 115 showed that PIEZO1, but not PIEZO2, is functionally expressed in juxtaglomerular cells, activation of which increases intracellular calcium level and results in decreased levels of renin synthesis and secretion. Calcium mobilization induced by mechanical stress using microfluidics is reduced in PIEZO1-KO juxtaglomerular cells, 115 yet not completely abolished, suggesting that other proteins, including TRPV4, 116 may also contribute to mechanosensation. Mechanistically, the Ptgs2 (COX-2)-PGE2-EP1/3 (prostaglandin-endoperoxide synthase 2/cyclooxygenase 2 PGE2 receptor 1/3) pathway has been proposed to mediate PIEZO1 activation-induced renin downregulation.…”

Renin Cells, From Vascular Development to Blood Pressure Sensing

“…Application of microfluidic mechanical stress to As4.1 cells resulted in intracellular calcium increased in wild-type but not in Piezo1 knockout cells. 80 Additionally, it has been reported that glomerular mesangial cells and renin-producing cells express Piezo2, which was upregulated with renin overproduction in renin-producing cells in response to dehydration as a mechanical load reduction. 81 Whether in vivo loss of function of either Piezo1 or 2 affects renin expression remains to be determined.…”

“…[77][78][79] Recent studies have suggested an association between piezo channels and renin cells. For instance, Yang et al 80 reported that Piezo1 colocalized with renin in mouse kidneys and activated Piezo1 downregulated renin in the renin-expressing As4.1 mouse tumoral cell line. Application of microfluidic mechanical stress to As4.1 cells resulted in intracellular calcium increased in wild-type but not in Piezo1 knockout cells.…”

Connexin 43 hemichannels and prostaglandin E2 release in anabolic function of the skeletal tissue to mechanical stimulation

“…The activation of the Piezo1 leads to an increase in intracellular Ca 2+ and the opening of Cx43 hemichannels through PI3K-AKT pathway in osteocytes ( Zeng et al, 2022 ). Interestingly, the release of PGE 2 is upregulated when Piezo1 is activated by either agonist or mechanical stretch ( Li et al, 2019 ; Yang et al, 2022 ). The PGE 2 release by Cx43 hemichannels is also regulated by extracellular ATP.…”