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

Background 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.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with zinc sulfate (ZnSO4) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 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, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions 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-κB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

Impact of Toll-like receptor signalling on urinary tract infection.

Toll-like receptors (TLRs), components of the innate immune system, play a pivotal role in the pathogenesis of urinary tract infection (UTI). TLRs (especially TLR4) expressed both by epithelial and non-epithelial cells, e.g. monocytes, initiate appropriate immune and inflammatory responses to defend and overcome microbial invasion and infection. Virulent uropathogenic strains (Escherichia coli) express P fimbriae, which bind to glycolipid receptors of uroepithelial and kidney tubular cells, triggering TLR4 activation with subsequent recruitment of leukocytes and release of pro-inflammatory cytokines. Tamm-Horsfall glycoprotein (uromucoid), a kidney-specific glycoprotein, not only binds to fimbriated E. coli and activates complement and dendritic cells, but also apparently shows an immunoregulatory function in UTI via a TLR4-dependent mechanism. Dysregulation of TLR and chemokine candidate genes (e.g. CXCR1) might predispose patients to chronic recurrent UTI. TLR antagonists and agonists can influence host defence mechanisms, and some of these immunomodulating agents may help to overcome intrinsic disturbances of the TLR system to offer new therapeutic options in UTI.

Calculated withdrawal of low-dose immunosuppression based on a detailed immunological monitoring after kidney transplantation between monocygotic twins.

BACKGROUND: Pretransplant screening in living donor kidney transplantation includes human leukocyte antigen matching, and panel reactive antibody analysis, whereas T cell mediated anti-donor reactivity is not assessed routinely. We investigated T cell reactivity after living related kidney transplantation between two monocygotic twins and in consequence correlated the withdrawal of individual immunosuppressive medication with immunological findings. METHODS: Immunosuppression consisted of mycophenolate mofetil, glucocorticoid single shot, and induction therapy with antithymocyte immunoglobulin. RESULTS: FACS analysis of recipient peripheral blood cells revealed a normal haemogram after transplantation, showing non-activated CD4 and CD8 cells. Mixed lymphocyte reaction did not reveal donor-specific T cell activity. IFN-gamma and IL-10 ELISA of supernatants of recipient cells cocultivated with donor cells support the lack of Th1 and Th2 cell differentiation. CONCLUSION: Based on immunological findings on days 5 and 20 MMF-therapy was reduced and stopped. Immunological monitoring on day 90 confirmed the absence of immune reactions directed against donor tissue.

Impact of different immunosuppressive regimens on antigen-presenting blood cells in kidney transplant patients.

BACKGROUND: Alloantigen-specific and unspecific immune processes contribute to chronic renal graft dysfunction. Despite 'optimized immunosuppressive therapy' (IS), the role of chronic cell activation still remains open. METHODS: 69 kidney transplant recipients (NTX) were assessed for monocyte surface antigens CD14 (LPS receptor) and CD16 (Fc-gamma-III receptor) by flow cytometry including the percentage amount of the proinflammatory CD14+CD16+ subset. 14 non-dialysis patients with chronic renal failure (CRF) and 24 healthy persons served as controls. RESULTS: All 14 patients suffering from CRF revealed higher CRP serum levels compared to healthy controls (p = 0.01). NTX patients had a (not significant) tendency to higher CRP concentrations (p > 0.05). The mean expression of CD14 on monocytes (mCD14) was lower in patients with CRF and in NTX patients (p = 0.024-p = 0.026). NTX patients revealed low expression of monocytic CD14 with no difference between the single IS therapy groups. The proinflammatory monocyte subpopulation positive for CD14 and CD16 was elevated both in uremic and NTX patients (p < 0.002), despite long-lasting IS therapy. CONCLUSIONS: Continuing IS therapy, even under 'optimized' drug-monitoring conditions, does not sufficiently prevent or suppress a microinflammatory (and potential fibrotic growth-promoting) status in NTX patients.