The chloride intracellular channel 5A stimulates podocyte Rac1, protecting against hypertension-induced glomerular injury

Abstract

Glomerular capillary hypertension elicits podocyte remodeling and is a risk factor for the progression of glomerular disease. Ezrin, which links podocalyxin to actin in podocytes, is activated through the chloride intracellular channel 5A (CLIC5A)-dependent phosphatidylinositol 4,5 bisphosphate (PI[4,5]P2) accumulation. Because Rac1 is involved in podocyte actin remodeling and can promote PI[4,5]P2 production we determined whether CLIC5A-dependent PI[4,5]P2 generation and ezrin activation are mediated by Rac1. In COS7 cells, CLIC5A expression stimulated Rac1 but not Cdc42 or Rho activity. CLIC5A also stimulated phosphorylation of the Rac1 effector Pak1 in COS7 cells and in cultured mouse podocytes. CLIC5A-induced PI[4,5]P2 accumulation and Pak1 and ezrin phosphorylation were all Rac1 dependent. In DOCA/Salt hypertension, phosphorylated Pak increased in podocytes of wild-type, but not CLIC5-deficient mice. In DOCA/salt hypertensive mice lacking CLIC5, glomerular capillary microaneurysms were more frequent and albuminuria was greater than in wild-type mice. Thus, augmented hypertension-induced glomerular capillary injury in mice lacking CLIC5 results from abrogation of Rac1-dependent Pak and ezrin activation, perhaps reducing the tensile strength of the podocyte actin cytoskeleton.

Role of Podocyte Injury in Glomerulosclerosis

“…Podocytes cultured in vitro are sensitive to shear stress, which induces reorganization of cytoskeleton (Friedrich et al 2006), and this helps them to cover an expanding GBM which further leads to foot process effacement. In desoxycorticosterone-trimethylacetate (DOCA) hypertensive mice, chloride intracellular channel 5A, which is highly enriched in podocytes foot process, protects against hypertension-induced podocyte injury through weakening the tensile strength of the actin cytoskeleton in Rac1-dependent manner (Tavasoli et al 2016). This has been considered to be the protective response for podocyte to escape detachment.…”

Pharmacogenomics of amlodipine and hydrochlorothiazide therapy and the quest for improved control of hypertension: a mini review

“… Caucasian [ 69 ] CLIC5 rs321329 SNP influenced response to hydrochlorothiazide treatment, 45722988A/G. Caucasian [ 67 , 70 ] CSMD1 and CUB rs2776546 and rs11993031 AA genotype increased BP response to HCTZ compared to AT and TT genotype. Caucasian [ 69 ] DOT1L rs2269879 SNP was strongly associated with greater SBP and DBP blood in Caucasians.…”

The cytoskeleton as a novel target for treatment of renal fibrosis

“…This suggests that, in addition to a role in protecting against TGF--induced increases in glomerular permeability (Dahly-Vernon et al, 2005), it may regulate podocyte function via the actin network. Other pathways that regulate the actin cytoskeleton in podocytes include chloride intracellular channel 5A (Wegner et al, 2010); hypertension-induced albuminuria was worse in mice with a knockout of this channel (Tavasoli et al, 2016). The Wilms tumor 1-interacting protein regulates actin in podocytes (Sedor et al, 2011;Kim et al, 2012), however, manipulation of this pathway has not yet been examined for anti-fibrotic or renoprotective effects.…”