Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies.
With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca(2+))-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier. This discovery provided an important missing piece in our understanding of the pathomechanism of filter barrier damage, revealing Ca(2+) signaling as critical for podocyte health and disease. The identification of the two Ca(2+) permeant channels TRPC5 and TRPC6 as mediators of this pathway not only bolstered the importance of podocyte cytoskeleton dynamics but also revealed promising drug targets for treatment-resistant nephrotic syndrome. This review will focus on this novel signaling pathway in primary podocytopathies and its implications for next-generation therapies for glomerular disease.
Renal Division, Department of Medicine and Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Nicolas
N
Wieder
Renal Division, Department of Medicine and Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. agreka@bwh.harvard.edu.|Broad Institute of MIT and Harvard, Cambridge, MA, USA. agreka@bwh.harvard.edu.
Anna
A
Greka
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002648:Child; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009404:Nephrotic Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D050052:TRPC Cation Channels / Q000378:metabolism*
D050052:TRPC Cation Channels; D002118:Calcium
Angiotensin type 1 receptor (ATR1); Calcium; Children; Cytoskeleton; Glomerular disease; Podocytopathies; Steroid-resistant nephrotic syndrome; TRPC channels