ArticleAmerican journal of physiology. Renal physiology2014
Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity.
Article in American journal of physiology. Renal physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy.Journal of the American Society of Nephrology : JASN · 2016Trial
- Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice.Hypertension (Dallas, Tex. : 1979) · 2025Article
- Podocyte specific knockout of the natriuretic peptide clearance receptor is podocyte protective in focal segmental glomerulosclerosis.PloS one · 2025Article
- The roles of TRPC6 in renal tubular disorders: a narrative review.Renal failure · 2024Review
- Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.Scientific reports · 2024Article
- β-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage.Clinical science (London, England : 1979) · 2023Article
- Ion channels and channelopathies in glomeruli.Physiological reviews · 2023Review
- Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury.International journal of molecular sciences · 2021Article
- Review
- Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease.British journal of pharmacology · 2020Review
- Review
- TRPC Channels in Proteinuric Kidney Diseases.Cells · 2019Review
- TRPC6 Binds to and Activates Calpain, Independent of Its Channel Activity, and Regulates Podocyte Cytoskeleton, Cell Adhesion, and Motility.Journal of the American Society of Nephrology : JASN · 2019Article
- Regulation of cofilin phosphorylation in glomerular podocytes by testis specific kinase 1 (TESK1).Scientific reports · 2018Article
- The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective.International journal of molecular sciences · 2018Review
- The mechanism of attenuation of epithelial-mesenchymal transition by a phosphodiesterase 5 inhibitor via renal klotho expression.Clinical and experimental pharmacology & physiology · 2018Article
- Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview.Journal of cardiovascular translational research · 2017Review
- Sildenafil Prevents Podocyte InjuryJournal of the American Society of Nephrology : JASN · 2017Article
- The Use of Sildenafil for Glomerular Disease.Journal of the American Society of Nephrology : JASN · 2017Article
- Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function.Journal of the American Society of Nephrology : JASN · 2017Article
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr(69)/Thr(70) (Thr(69) in mice and Thr(70) in humans) and Ser(321)/Ser(322) (Ser(321) in mice and Ser(322) 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 Thr(69) in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. 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 S-nitroso-N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41-2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3',4'-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr(69) dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30-60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.