Paricalcitol Inhibits Renal Inflammation by Promoting Vitamin D Receptor–Mediated Sequestration of NF-κB Signaling

Abstract

Inflammation is a pathologic feature of a variety of chronic kidney diseases. Several lines of evidence suggest a potential anti-inflammatory role for vitamin D in chronic kidney disease, but the underlying mechanism remains unknown. Here, the effect of the synthetic vitamin D analogue paricalcitol on renal inflammation was investigated in a mouse model of obstructive nephropathy. Paricalcitol reduced infiltration of T cells and macrophages in the obstructed kidney. This inhibition of inflammatory cell infiltration was accompanied by a decreased expression of RANTES and TNF-␣. Induction of RANTES was localized primarily to the tubular epithelium, underscoring a role for tubular cells in renal inflammation. In a human proximal tubular cell line (HKC-8), paricalcitol inhibited RANTES mRNA and protein expression and abolished the ability of tubular cells to recruit lymphocytes and monocytes after TNF-␣ stimulation. Although RANTES induction depended on NF-B signaling, paricalcitol affected neither TNF-␣-mediated IB␣ phosphorylation and degradation nor p65 NF-B activation and nuclear translocation. Instead, chromatin immunoprecipitation assay showed that paricalcitol abolished the binding of p65 to its cognate cis-acting element in the RANTES promoter. The vitamin D receptor (VDR) and p65 formed a complex in tubular cells after paricalcitol treatment, which inhibited the ability of p65 to trans-activate gene transcription. In vivo, paricalcitol did not block NF-B nuclear translocation after obstructive injury but did increase the expression and nuclear distribution of VDR. These results suggest that paricalcitol inhibits renal inflammatory infiltration and RANTES expression by promoting VDRmediated sequestration of NF-B signaling.

Vitamin D, Proteinuria, Diabetic Nephropathy, and Progression of CKD

“…For example, in vitro, 1,25(OH) 2 D attenuates TNF-␣-induced monocyte chemoattractant protein 1 (MCP-1) expression by human proximal tubule cells (15). A synthetic VDRA, paricalcitol, inhibits renal inflammation by promoting VDRmediated sequestration of NF-B signaling (16). Although cell surface receptor-mediated, nongenomic pathways (17,18) are described, the potent antiproliferative, prodifferentiative, and immunomodulating activities (17,19,20) seem to be modulated via vitamin D receptor-dependent genomic effects; the latter seem to provide the biologic basis for salutary effects of VDRA in patients with kidney disease.…”

Adriamycin nephrotoxicity is reduced by metallothionein over-expression and kidney gene expression is modified by diabetes in the OVE26 diabetic model.

“…Several clinical studies discovered the declining renal function is closely related to the extent of inflammation in CKD patients [67]. Vitamin D deficiency is observed as an early pathological feature ofCKD [68]. In nephropathy patients, there is a significant correlation between expression of CYP27B 1, the rating limiting enzyme for formation of active vitamin D and renal inflammation [69].…”

Pleiotropic Effects of Vitamin D in Kidney Disease

“…Renoprotective effects of vitamin D has been identified in several AKI animal models, including contrast-induced AKI, gentamicin-induced AKI, cisplatin-induced AKI, cyclosporine-induced AKI, ischemia-/reperfusion-induced AKI, and the obstructive nephropathy model [95][96][97][98][99]. The data from experimental AKI studies suggest that vitamin D analogs protect the kidney by targeting three major pathways: the local RAS, antioxidation, NF-κB and PPAR-γ pathways to suppress inflammatory, fibrotic, apoptotic, and proliferative factors [95,[100][101][102]. In contrast to the role of vitamin D in CKD patients, the role of vitamin D in AKI is not as well defined.…”