Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB

Abstract

The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear. We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD. In cultured VSMCs, treatment with zinc sulfate (ZnSO) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-B activation. ZnSO increased the abundance of zinc-finger protein TNF--induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-B pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO under high phosphate conditions. mice showed reduced plasma zinc levels, and ZnSO supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO ameliorated the osteoinductive effects of uremic serum in VSMCs. Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-B pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

“…Because vascular calcification is preferentially associated with advanced-stage CVD, we focused on the mechanisms of AACOCF3 in this process. Vascular calcification is mediated mainly by osteogenic/chondrogenic reprogramming of VSMCs in response to various triggers, especially hyperphosphatemia (14,23). In liver tissue, excessive phosphate intake in rats is associated with increased AA concentrations (24).…”

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

“…Serum was obtained by immediate centrifugation and stored at -80°C. HAoSMCs were serum-starved for 24 hours prior to treatment for 24 hours with 15% uremic serum from hemodialysis patients (uremic serum) or control serum from matched healthy individuals (normal serum) collected as described previously (30). Serum calcification propensity was analyzed by determination of the one-half maximal transition time (T 50 ) of in vitro transformation from primary to secondary calciprotein particles (30) as described by Pasch et al (53) using a Nephelostar Plus nephelometer (BMG Labtech).…”

“…Taken together, these observations indicate that Sgk1 inhibition by EMD638683 ameliorates aortic osteoinductive signaling, vascular calcification, and vascular stiffness in the cholecalciferol overload mouse model. from hemodialysis patients before dialysis (30) and from healthy volunteers and HAoSMCs were exposed to uremic serum (US) or normal serum (NS) (Supplemental Table 5). Serum calcification propensity (30) measured as calciprotein particle maturation time (T 50 ) was significantly higher in uremic serum than in normal serum (Supplemental Table 5).…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…As a negative acute phase protein, low levels of fetuin A indicate systemic inflammation and may shorten telomeres in leukocytes [23]. Furthermore, high Pi induces the expression of the proinflammatory transcription factor NF-κB in human aortic VSMC [24]. Figure 1.…”