Synaptopodin Limits TRPC6 Podocyte Surface Expression and Attenuates Proteinuria
Open Access
- 28 March 2016
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 27 (11), 3308-3319
- https://doi.org/10.1681/asn.2015080896
Abstract
Gain-of-function mutations of classic transient receptor potential channel 6 (TRPC6) were identified in familial FSGS, and increased expression of wild-type TRPC6 in glomeruli is observed in several human acquired proteinuric diseases. Synaptopodin, an actin binding protein that is important in maintaining podocyte function, is downregulated in various glomerular diseases. Here, we investigated whether synaptopodin maintains podocyte function by regulating podocyte surface expression and activity of TRPC6. We show indirect interaction and nonrandom association of synaptopodin and TRPC6 in podocytes. Knockdown of synaptopodin in cultured mouse podocytes increased the expression of TRPC6 at the plasma membrane, whereas overexpression of synaptopodin decreased it. Mechanistically, synaptopodin–dependent TRPC6 surface expression required functional actin and microtubule cytoskeletons. Overexpression of wild–type or FSGS–inducing mutant TRPC6 in synaptopodin-depleted podocytes enhanced TRPC6–mediated calcium influx and induced apoptosis. In vivo, knockdown of synaptopodin also caused increased podocyte surface expression of TRPC6. Administration of cyclosporin A, which stabilizes synaptopodin, reduced LPS-induced proteinuria significantly in wild-type mice but to a lesser extent in TRPC6 knockout mice. Furthermore, administration of cyclosporin A reversed the LPS-induced increase in podocyte surface expression of TRPC6 in wild-type mice. Our findings suggest that alteration in synaptopodin levels under disease conditions may modify intracellular TRPC6 channel localization and activity, which further contribute to podocyte dysfunction. Reducing TRPC6 surface levels may be a new approach to restoring podocyte function.Keywords
This publication has 36 references indexed in Scilit:
- A novel TRPC6mutation in a family with podocytopathy and clinical variabilityBMC Nephrology, 2013
- Insulin increases surface expression of TRPC6 channels in podocytes: role of NADPH oxidases and reactive oxygen speciesAmerican Journal of Physiology-Renal Physiology, 2012
- Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heartNature Communications, 2012
- Tyrosine phosphorylation–dependent activation of TRPC6 regulated by PLC-γ1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosisMolecular Biology of the Cell, 2011
- Antagonistic Regulation of Actin Dynamics and Cell Motility by TRPC5 and TRPC6 ChannelsScience Signaling, 2010
- A Novel TRPC6 Mutation That Causes Childhood FSGSPLOS ONE, 2009
- TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcriptionAmerican Journal of Physiology-Cell Physiology, 2009
- Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation*Online Journal of Public Health Informatics, 2008
- Canonical Transient Receptor Potential Channel (TRPC) 3 and TRPC6 Associate with Large-Conductance Ca2+-Activated K+(BKCa) Channels: Role in BKCaTrafficking to the Surface of Cultured PodocytesMolecular Pharmacology, 2008
- TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal functionNature Genetics, 2005