Phosphodiesterase V Inhibition Ameliorates Angiontensin II-induced Podocyte Dysmotility via the Protein Kinase G-mediated Downregulation of TRPC6 Activity.

Phosphodiesterase V Inhibition Ameliorates Angiontensin II-induced Podocyte Dysmotility via the Protein Kinase G-mediated Downregulation of TRPC6 Activity.
Am J Physiol Renal Physiol. 2014 Apr 16;
Authors: Hall G, Rowell J, Farinelli F, Gbadegesin RA, Lavin P, Wu G, Homstad A, Malone AF, Lindsey T, Jiang R, Spurney R, Tomaselli GF, Kass DA, Winn MP
Abstract
The emerging role of TRPC6 as a central contributor to various pathologic processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed protein kinase G (PKG) as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at 2 highly conserved amino acid residues, threonine 69 (Thr69 in murines; Thr70 in humans) and serine 321 (Ser321 in murines; Ser322 in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr69 in non-stimulated podocytes but this declined upon angiotensin II (Ang II) stimulation or overexpression of a constitutively active calcineurin phosphatase (CA-Cn). Ang II induced podocyte motility in an in vitro wound-assay, and this was reduced 30-60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG (p<0.05). Pretreatment of podocytes with the PKG agonists SNAP (NO-do...

Source: Am J Physiol Renal P... - April 16, 2014 Category: Urology & Nephrology Authors: Hall G, Rowell J, Farinelli F, Gbadegesin RA, Lavin P, Wu G, Homstad A, Malone AF, Lindsey T, Jiang R, Spurney R, Tomaselli GF, Kass DA, Winn MP Tags: Am J Physiol Renal Physiol Source Type: research