Balancing calcium signals through TRPC5 and TRPC6 in podocytes

ArticleinJournal of the American Society of Nephrology 22(11):1969-80 · November 2011with28 Reads
DOI: 10.1681/ASN.2011040370 · Source: PubMed
Abstract
Calcium (Ca(2+)) ions are important mediators of cellular homeostasis owing to their ability to elicit a dynamic, transient, and tightly regulated range of biochemical responses. More than a decade ago, a nonselective, Ca(2+)-permeable, cationic conductance was identified in podocytes downstream of angiotensin II (Ang II) signaling, but its molecular structure remained elusive. Six years ago, transient receptor potential canonical 6 (TRPC6) mutations were found in families with hereditary FSGS, and TRPC5 and TRPC6 channels are now known as the Ca(2+) influx pathways for this previously described, nonselective, cationic current in podocytes. Ang II activation engages this Ca(2+) influx to modulate the actin cytoskeleton in podocytes. These discoveries dovetail with previously described regulation of actin dynamics by the Ca(2+)-activated phosphatase, calcineurin, and the emergence of Rho GTPases as critical regulators of podocyte function in health and disease. Understanding the interconnected signaling regulated by Ca(2+) currents offers potential new therapeutic targets and highlights the notion that synergistic therapies targeting multiple levels of biochemistry may be useful in treating proteinuric kidney disease.
    • "Therefore, this may be a case in which a simple, initial glance at the genetics might seemingly point in the direction of blocking TRPC6, but a nuanced understanding of the physiology and cell biology may suggest that alternative strategies should be sought, ones that only attack inducible, and not homeostatic, Ca 2+ influx. Identification of the Ca 2+ -regulated phosphatase calcineurin as an important link between TRPC/Ca 2+ signaling and cytoskeletal dynamics in podocytes [20, 28] introduced a new view on the mechanism of action of cyclosporin A (CsA) in FSGS and other glomerular diseases. Instead of acting through its classical immunologic effect on NFAT signaling in T-cells, it appears to inhibit calcineurin in a podocyte-specific manner to protect the podocyte homeostatic structural protein synaptopodin from dephosphorylation and ultimate degrada- tion [38] . "
    [Show abstract] [Hide abstract] 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.
    Article · Oct 2015
    • "In podocytes, TRPC6 is a slit diaphragm-interacting protein [106] which may regulate changes in calcium ion (Ca 2+ ) levels and in actin cytoskeleton rearrangement [107]. Overexpression of TRPC6 in mice New anti-proteinuric strategies Target structures/pathways on podocytes Abatacept (CTLA-4–Ig) B7-1, integrin signalling [4, 93, 96] Adalimumab (Anti-TGF-β) T G F -β/SMAD, apoptosis [111] Amiloride (suPAR blocker) β3-integrin signalling [99, 100] Oral ManNAc Angptl 4 [116] Ruboxistaurin (selective PKC-β inhibitor) (Among others) extracellular matrix synthesis/ turnover [120, 121] Saquinavir (protease inhibitor) NF-κB/IκBα [122, 123] TRPC6 siRNA Ca 2+ levels, actin cytoskeleton rearrangement107108109110 Ig, Immunoglobulin; TGF-β, transforming growth factor beta, MAnNAc, N-acetyl-D-mannosamine; protein kinase C beta; TRPC6, transient receptor potential cation channel, subfamily C, member 6; siRNA, small interfering RNA; Angptl 4, angiopoietin-like 4; NF-κB/IκBα, nuclear factor kappa-light-chain-enhancer of activated B cells/inhibitor of kappa B Pediatr Nephrol induces glomerular disease [108]. In humans gain-of-function mutations in TRPC6 have been associated with familial forms of FSGS [109]. "
    [Show abstract] [Hide abstract] ABSTRACT: Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active inside-out signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.
    Full-text · Article · May 2015
    • "Recent studies further revealed a role of TRPC5 in podocytes, demonstrating that the pathogenic remodelling in proteinuria mouse models can be attributed to the activation of TRPC5 channels. Accordingly, TRPC5-deficient mice were less sensitive to LPS-induced albuminuria (Greka and Mundel, 2011; Schaldecker et al., 2013), making a pharmacological inhibition of TRPC5 a promising target to protect from the destruction of the glomerular filter barrier in kidney injury. Several inhibitors of TRPC5 activity have been published, such as SKF96356 and flufenamic acid. "
    [Show abstract] [Hide abstract] ABSTRACT: TRPC5 is a nonselective, Ca(2+) permeable cation channel which belongs to the large family of transient receptor potential channels. It is predominantly found in the central nervous system with a high expression density in the hippocampus, the amygdala and the frontal cortex. Several studies confirm that TRPC5 channels are implicated in the regulation of neurite length and growth cone morphology. We identified clemizole as a novel inhibitor of TRPC5 channels. Clemizole efficiently blocks TRPC5 currents and Ca(2+) entry in the low micromolar range (IC50 = 1.0 - 1.3 μM), as determined by fluorometric [Ca(2+)]i measurements and patch clamp recordings. Clemizole blocks TRPC5 currents irrespectively of the mode of activation, e.g. stimulation of GPCR, hypoosmotic buffer conditions or by the direct activator riluzole. Electrophysiological whole cell recordings revealed that the block was mostly reversible. Moreover, clemizole was still effective in blocking TRPC5 single channels in excised inside-out membrane patches, hinting to a direct block of TRPC5 by clemizole. Based on fluorometric [Ca(2+)]i measurements, clemizole exhibits a 6-fold selectivity for TRPC5 over TRPC4β (IC50 = 6.4 μM), the closest structural relative of TRPC5 and an almost 10-fold selectivity over TRPC3 (IC50 = 9.1 μM) and TRPC6 (IC50 = 11.3 μM). TRPM3 and M8 as well as TRPV1, V2, V3 and V4 channels were only weakly affected by markedly higher clemizole concentrations. Clemizole was not only effective in blocking heterologously expressed TRPC5 homomers but also TRPC1:TRPC5 heteromers as well as native TRPC5-like currents in the U-87 glioblastoma cell line.
    Full-text · Article · Aug 2014
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