Increased TRPC3 expression in vascular endothelium of patients with malignant hypertension

Abstract

An increased expression of transient receptor potential canonical type 3 (TRPC3) cation channels has been proposed as one of the factors contributing to the pathogenesis of hypertension. To test that hypothesis we compared the expression of TRPC3 and TRPC6 as an endogenous control in human vascular endothelium of preglomerular arterioles in kidney biopsies from six patients with malignant hypertension and from four patients with diarrhea-associated hemolytic-uremic syndrome. Patients with malignant hypertension showed significantly higher systolic blood pressure and more prominent expression of TRPC3 in vascular endothelium of preglomerular arterioles compared to patients with hemolytic-uremic syndrome. The expression of TRPC6 was not different between the two groups. The study supports the hypothesis that the increased expression of TRPC3 is associated with malignant hypertension in humans. Malignant hypertension is a hypertensive emergency with severe elevation of blood pressure, a Keith-Wagener-Barker grade III or IV hypertensive retinopathy, and acute impairment of renal function in most cases. In white subjects, essential hypertension accounts for approximately 30% of malignant hypertension, whereas in blacks essential hypertension is the predominant cause, accounting for approximately 82% of all cases. The characteristic pathological change of malignant hypertension represents endothelial injury. Its pathophysiology involves mechanical stress on the vessel wall, a proliferative endarteriitis in small arteries and arterioles, and fibrinoid necrosis with fine subendothelial droplets and hyalin thrombi formation.

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

“…Nonselective Ca 2+ permeant TRPC channels (more specifically, TRPC3) have been implicated in many cardiorenal diseases, such as cardiac hypertrophy [36][37][38][39]42 and hypertension. [28][29][30][31][33][34][35] Some studies showed a certain correlation with kidney disease. 27,32,50 However, no study to our knowledge has investigated the role of fibroblast TRPC3 in renal disease, such as fibrosis, and whether its inhibition could prevent the development of renal dysfunction.…”

“…25,26 TRPC3 is upregulated in kidney and monocytes from patients with hypertension and correlates with proinflammatory cytokines. [27][28][29][30][31] Increased TRPC3 channel protein expression is found in human monocytes from patients with CKD, 32 and association of TRPC3 with hypertension is increasingly being reported. [33][34][35] TRPC3 also promotes cardiac hypertrophy through calcineurin and NF of activated T cells [36][37][38][39] and mediates a proarrhythmic Ca 2+ entry in cardiac myocytes.…”

Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

“…TRPC channels activated by G-protein-coupled receptors (GPCRs) mediate [Ca 2+ ] i increase in vascular smooth muscle cells (VSMCs), which determine luminal diameter and contractility and thus peripheral resistance that markedly influences blood flow and pressure (12)(13)(14). In particular, accumulating evidence suggests that TRPC3 is up-regulated in hypertensive animal models (15), as well as in patients with hypertension (16)(17)(18), establishing a correlation between elevated TRPC3 activity and high blood pressure. Here, we report a molecular mechanism by which WNK4 regulates TRPC3 activity to determine vascular tone and its ablation by WNK4 mutations associated with hypertension.…”

Imbalance and dysfunction of transient receptor potential channels contribute to the pathogenesis of hypertension

“…Importantly, intracellular Ca 2+ homeostasis is essential for vascular function and blood pressure regulation as well as hormone secretion. Disturbance of intracellular Ca 2+ homeostasis has been reported in both experimental and human hypertension [3,4].…”

“…Store-operated Ca 2+ channels (SOCs, or capacitative Ca 2+ entry channels) are activated through IP 3 -induced Ca 2+ release and consequently deplete Ca 2+ from ER stores [5]. ER and sarcoplasmic reticulum (SR) stores are released through the stimulation of G-protein-coupled receptors, which activate phospholipase C, consequently generating IP 3 and activating the diacylglycerol (DAG) signal pathways. TRPCs (TRPC1-7), TRPC2, TRPC3, TRPC6 and TRPC7 have been reported to be activated by DAG [68].…”