TRPC6 and FSGS: The latest TRP channelopathy

Abstract

Focal and segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in children and adults throughout the world. In the past 50 years, significant advances have been made in the identification and characterization of familial forms of nephrotic syndrome and FSGS. Resultant to these pursuits, several podocyte structural proteins such as nephrin, podocin, alpha-actinin 4 (ACTN4), and CD2-associated protein (CD2AP) have emerged to provide critical insight into the pathogenesis of hereditary nephrotic syndromes. The latest advance in familial FSGS has been the discovery of a mutant form of canonical transient receptor potential cation channel 6 (TRPC6), which causes an increase in calcium transients and essentially a gain of function in this cation channel located on the podocyte cell membrane. The TRP ion channel family is a diverse group of cation channels united by a common primary structure which contains six membrane-spanning domains, with both carboxy and amino termini located intracellularly. TRP channels are unique in their ability to activate independently of membrane depolarization. TRPC6 channels have been shown to be activated via phospholipase C stimulation. The mechanisms by which mutant TRPC6 causes an increase in intracellular calcium and leads to glomerulosclerosis are unknown. Mutant TRPC6 may affect critical interactions with the aforementioned podocyte structural proteins, leading to abnormalities in the slit diaphragm or podocyte foot processes. Mutant TRPC6 may also amplify injurious signals mediated by Ang II, a common final pathway of podocyte apoptosis in various mammalian species. Current evidence also suggests that blocking TRPC6 channels may be of therapeutic benefit in idiopathic FSGS, a disease with a generally poor prognosis. Preliminary experiments reveal the commonly used immunosuppressive agent FK-506 can inhibit TRPC6 activity in vivo. This creates the exciting possibility that blocking TRPC6 channels within the podocyte may translate into long-lasting clinical benefits in patients with FSGS.

Recent advances of animal model of focal segmental glomerulosclerosis

“…Myosin 1e (Myo1e) is one of the two Src homology 3 domain-containing "long-tailed" type I myosins in Actin filament cross-linking protein/Interacts with integrins and strengthens the podocyte-GBM interaction Atypical protein kinase C [68][69][70][71] Tight junctions/Formation of Par complex and interacts with slit diaphragm Rhophilin-1 [80] Rho GTPase activating protein 24 [80] Cytoplasm/Rho GTPase-interacting protein, integrity of glomerular filtration barrier Angiotensin II receptor [55][56][57] Angiotensin-converting enzyme [55][56][57] Membrane/pseudocyst formation at podocyte CD2-associated protein [65][66][67] CD2-associated protein [64] Insertion site of the slit diaphragm/Formation SD complex with podocin and nephrin Laminin subunit beta-2 [81][82][83][84] Laminin subunit beta-2 [81][82][83][84] Podocyte anchoring and differentiation in GBM microRNA 193α [74,75] Cytoplasm/Inhibition of expression of WT-1 Myosin 1e [49,50] Myosin 1e [49,50] Actin binding long-tailed motor protein/Regulation of actin cytoskeleton Nuclear factor of activated T cells [76,77] Transient receptor potential 6 [53,54] Membrane/the activation of calcineurin-NFAT/Wnt signaling via the increased calcium influx Podocin [46] Podocin [58,59] Insertion site of the SD/SD assembly and maintaining the signaling of nephrin Shroom family member 3 …”

“…This mutation leads to a gain of function and a transient increase of intracellular calcium concentration [53]. Krall et al described the generation and phenotypic characterization of three different transgenic mice lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS.…”

Ion channels in cancer: future perspectives and clinical potential

“…Apoptosis-stimulating Ca 2þ channels or unselective cation channels include NMDA receptors [73], purinergic receptors [74,75], as well as the TRP channels [76] TRPC1 [77], TRPC3 [78], TRPC6 [79][80][81] In glioma cells, TRPC1 is required for cytokinesis in proliferation and migration [95,96]. Ca 2þ entry through TRPM8 channels leads to the activation of Ca 2þ -sensitive K þ channels (KCa1.1), which participate in the machinery accomplishing migration [5,97].…”

254C>G: a TRPC6 promoter variation associated with enhanced transcription and steroid-resistant nephrotic syndrome in Chinese children

“…In addition, these gene mutations have been shown to be associated with a reduced incidence of relapse of proteinuria upon renal transplantation (13). One of these proteinuria candidate genes, canonical transient receptor potential channel 6 (TRPC6), encodes TRPC6 protein, a Ca 2+ -permeable nonselective cation channel, which is a member of the transient receptor potential channel subfamily (10). In 2005, Winn et al first identified TRPC6 variants segregated with the development of familial FSGS.…”

“…These proteins have been proven essential for the signaling initiated from the slit diaphragm, which is the key component of the glomerular filtration barrier (10). Therefore, these mutations may contribute to disrupted filtration function and increased protein permeability.…”