Gyarmati, Georgina and Toma, Ildikó and Izuhara, A. and Burford, J. L. and Shroff, U. N. (2022) The role of TRPC6 calcium channels and P2 purinergic receptors in podocyte mechanical and metabolic sensing. Physiology International, 109 (1). pp. 31-45. ISSN 2498-602X
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Abstract
Podocyte calcium (Ca2+) signaling plays important roles in the (patho)physiology of the glomerular filtration barrier. Overactivation of podocyte transient receptor potential canonical (TRPC) channels including TRPC6 and purinergic signaling via P2 receptors that are known mechanosensors can increase podocyte intracellular Ca2+ levels ([Ca2+]i) and cause cell injury, proteinuria and glomerular disease including in diabetes. However, important mechanistic details of the trigger and activation of these pathways in vivo in the intact glomerular environment are lacking. Here we show direct visual evidence that podocytes can sense mechanical overload (increased glomerular capillary pressure) and metabolic alterations (increased plasma glucose) via TRPC6 and purinergic receptors including P2Y2. Multiphoton microscopy of podocyte [Ca2+]i was performed in vivo using wild-type and TRPC6 or P2Y2 knockout (KO) mice expressing the calcium reporter GCaMP3/5 only in podocytes and in vitro using freshly dissected microperfused glomeruli. Single-nephron intra-glomerular capillary pressure elevations induced by obstructing the efferent arteriole lumen with laser-induced microthrombus in vivo and by a micropipette in vitro triggered >2-fold increases in podocyte [Ca2+]i. These responses were blocked in TRPC6 and P2Y2 KO mice. Acute elevations of plasma glucose caused >4-fold increases in podocyte [Ca2+]i that were abolished by pharmacological inhibition of TRPC6 or P2 receptors using SAR7334 or suramin treatment, respectively. This study established the role of Ca2+ signaling via TRPC6 channels and P2 receptors in mechanical and metabolic sensing of podocytes in vivo, which are promising therapeutic targets in conditions with high intra-glomerular capillary pressure and plasma glucose, such as diabetic and hypertensive nephropathy. © 2021 The Author(s).
| Item Type: | Article |
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| Additional Information: | Export Date: 26 April 2022 Correspondence Address: Peti-Peterdi, J.; Department of Physiology and Neuroscience, 1501 San Pablo Street, ZNI 335, United States; email: petipete@usc.edu Chemicals/CAS: glucose, 50-99-7, 84778-64-3; immunoglobulin M, 9007-85-6; mannitol, 69-65-8, 87-78-5; suramin, 129-46-4, 145-63-1 Manufacturers: Sigma Aldrich; TocrisLeica Microsystems, Germany Funding details: National Institutes of Health, NIH, DK100944, S10OD021833 Funding details: University of South Carolina, USC Funding text 1: This work was supported in part by US National Institutes of Health grants DK100944 to J.P-P. Fluorescence imaging was performed at the USC Multi-Photon Microscopy Core funded by the National Institute of Health grant S10OD021833. |
| Uncontrolled Keywords: | Female; Male; immunohistochemistry; ARTICLE; MOUSE; diabetes mellitus; Electrophysiology; immunoblotting; controlled study; HYPERTENSION; GLUCOSE; animal tissue; animal model; animal experiment; synaptic transmission; Immunoglobulin M; ophthalmoscopy; hyperglycemia; mannitol; protein expression; immunofluorescence; calcium channel; knockout mouse; Fluorescence microscopy; Calcium Signaling; SURAMIN; confocal microscopy; Connexin 43; glomerulus capillary; Hypertensive nephropathy; presynaptic nerve; transient receptor potential channel 6; podocyte; podocyte; multiphoton microscopy; multiphoton microscopy; intravital imaging; fetal bovine serum; purinergic P2Y2 receptor; P2Y2; plasma osmolality; capillary pressure; TRPC6; glomerular filtration barrier; |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 29 Jun 2022 13:13 |
| Last Modified: | 29 Jun 2022 13:13 |
| URI: | http://real.mtak.hu/id/eprint/144284 |
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