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-alpha. 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-alpha stimulation. Although
RANTES induction depended on
NF-kappaB signaling,
paricalcitol affected neither
TNF-alpha-mediated
IkappaB alpha phosphorylation and degradation nor p65
NF-kappaB 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-kappaB 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 VDR-mediated sequestration of
NF-kappaB signaling.