Seminar: Prof. Stuart Dryer

Multimodal gating of podocyte TRPC6 channels and dysregulation in a rodent model of FSGS

Date:
10 June 2014 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Multimodal gating of podocyte TRPC6 channels and dysregulation in a rodent model of FSGS
Speaker(s):

Prof. Stuart Dryer, Dept. of Biology and Biochemistry, University of Houston, Texas, USA

Host(s):

Dr. Johan van der Vlag en Dr. Tom Nijenhuis, Dept. of  Nephrology,  Radboudumc 

10-06-2014 00:00:00Europe/AmsterdamMultimodal gating of podocyte TRPC6 channels and dysregulation in a rodent model of FSGS  Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

Dryer , StuartTRPC6 channels were implicated by studies of genetic forms of FSGS nearly a decade ago, suggesting that a gain of function of these channels drives progression of FSGS, and very possibly other kidney diseases as well. TRPC6 mutations are relatively rare, and FSGS of other etiologies is much more common. This talk will describe electrophysiological and biochemical work to characterize regulation of endogenous TRPC6 channels, exhibiting multi-modal gating in podocytes. 

This includes: (1) Canonical lipid pathways that are mediated by products of phospholipase signaling produced during G protein-coupled signal cascades, specifically diacylglycerol and 20-HETE. These pathways are engaged by Ang II acting through AT1 receptors, and by ATP acting on various P2Y receptors. (2) Direct mechanical activation of the TRPC6 channel complex. Virtually any stimulus that causes deformation or stretch of the plasma membrane in either direction activates TRPC6 in podocytes.

In addition, oxidative modulation occurs when locally generated reactive oxygen species (ROS) stimulate an increase in TRPC6 levels on the cell surface. In podocytes, ROS are generated by NADPH oxidases that physically interact with TRPC6, and there may be additional sources, for example during hyperglycemia. Oxidative modulation contributes to TRPC6 activation during G protein-mediated signaling by Ang II and ATP. By contrast, oxidative effects are not required for mechanical activation of TRPC6. Podocin plays an important role in regulating TRPC6 gating in podocytes. Podocin knockdown markedly increases mechanical activation of TRPC6, but reduces or eliminates activation by canonical lipid signals, or by G protein mediated cascades. 

We have examined TRPC6 gating in podocytes in glomeruli isolated from rats treated for 90 days with puromycin aminonucleoside (PAN), a well-established model for acquired (secondary) FSGS. Podocytes in these glomeruli exhibit markedly elevated mechanical activation of TRPC6, but much reduced activation by a G protein pathway. PAN-treated rats have increased glomerular TRPC6 protein, but markedly decreased podocin. Alterations in TRPC6 gating, including increased activation by mechanical stimuli, may therefore be a causative factor in acquired forms of FSGS. These observations suggest therapeutic strategies based on inhibition of this response.

Key Publications:

  • ATP acting through P2Y receptors causes activation of podocyte TRPC6 channels: role of podocin and reactive oxygen species. Am J Physiol Renal Physiol 306, 2014
  • A mutation in TRPC6 channels abolishes their activation by hypoosmotic stretch but does not affect activation by diacylglycerol or G protein signaling cascades. Am J Physiol Renal Physiol 306, 2014 
  • Angiotensin II activation of TRPC6 channels in rat podocytes requires generation of reactive oxygen species.  Journal of Cellular Physiology 229, 2013
  • NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: Essential role of podocin in formation of this complex.  American Journal of Physiology - Cell Physiology 305, 2013  
  • Opposing effects of podocin on the gating of podocyte TRPC6 channels evoked by membrane stretch or diacylglycerol.  American Journal of Physiology-Cell Physiology 305, 2013
 







 



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