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Review
. 2016 Jul;31(7):1047-54.
doi: 10.1007/s00467-015-3224-1. Epub 2015 Oct 21.

Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies

Nicolas Wieder  1 , Anna Greka  2   3
Affiliations
Review

Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies

Nicolas Wieder et al. Pediatr Nephrol. 2016 Jul.

Abstract

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.

Keywords: Angiotensin type 1 receptor (ATR1); Calcium; Children; Cytoskeleton; Glomerular disease; Podocytopathies; Steroid-resistant nephrotic syndrome; TRPC channels.

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Figures

Fig. 1
Fig. 1
Simplified schematic presentation of our current understanding of TRPC channels in podocytes in health and disease. TRPC6 has a homeostatic function, maintaining a functioning podocyte cytoskeleton through RhoA activation and thus an intact filter barrier. Increased activity (e.g., gain-of-function mutations) disrupts cytosolic Ca2+ homeostasis and is known to cause focal segmental glomerulosclerosis (FSGS). In contrast, TRPC5 is inducible and activates Rac1, which has been shown to cause cytoskeletal collapse and consecutive filter barrier damage
Fig. 2
Fig. 2
Current standard treatment options for primary podocytopathies (Conventional Treatment) and podocyte-targeted, cytoskeleton protective treatment (Targeted Treatment). Calcineurin inhibitors have been used as second-line therapy for corticosteroid-resistant FSGS on an empiric basis. The finding that calcineurin inhibitors prevent synaptopodin cleavage makes it also a cytoskeleton protective agent
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