Abstract: TH-OR82
Piezo1 Participates the Mechanosensation of Juxtaglomerular Cells and Regulates Renin Production In Vitro and In Vivo
Session Information
- Mechanisms of Hypertension and Cardiorenal Disease: From the Vasculature to the Gut
November 02, 2023 | Location: Room 108, Pennsylvania Convention Center
Abstract Time: 04:39 PM - 04:48 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Zhou, Yiming, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Yang, Xiaoqiang, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Wang, Le, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Luo, Siweier, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
Background
Renin is a key rate-limiting enzyme in RAS system, which is closely related to water and salt metabolism and the development of cardiovascular diseases such as hypertension. 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. Recent studies identified the nonselective cation channels Piezo1 as a novel mechanosensitive ion channel which plays an important role in various physiological functions. However, whether Piezo1 channels regulates renin expression remains undetermined.
Methods
In this study, we determined the expression and subcellular localization of Piezo1 in JG cells by qPCR, Western blot, Immunohistochemistry. Then, a Fluo-4 AM-based calcium-imaging system was used to detect the dynamic changes of intracellular calcium in response to Piezo1 specific agonist Yoda1 and mechanical stress (MS)-induced by perfusion. Piezo1 knockout JG cells abolished Yoda1-induced effect. Then, we used RNA-seq experiment to investigate the downstream signaling of Piezo1 in JG cells. Finally, we generated adeno-associated virus (AAV)-mediated kidney-specific Piezo1 knockdown mice to investigate the in vivo effect of Piezo1.
Results
We found that the calcium permeable ion channel Piezo1 was expressed in JG cells in mouse kidney slides as well as mouse JG cells. Activation of Piezo1 by its agonist Yoda1 and MS induced an intracellular calcium increase and reduced the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Mechanistically, RNAseq assay demonstrated that activation of Piezo1 upregulated the PTGS2 expression via the calcineurin-NFAT pathway and increased the production of PTGS2 (COX-2) and PGE2 in JG cells, which inhibited cAMP production and reduced renin expression in JG cells. In animal models, we demonstrated that activation of Piezo1 significantly downregulated the blood pressure in wildtype but not kidney-specific Piezo1 knockdown mice.
Conclusion
In summary, these results revealed that activation of Piezo1 could regulate the renin expression in vitro and in vivo, subsequently reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system.