1,25-dihydroxyvitamin D3 inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression

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243

194

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.

Section: Discussionmentioning

confidence: 99%

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

Tan

Wen

Liu

2008

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243

194

“…Reverse transcriptase-PCR was performed as described elsewhere (24). Briefly, the first-strand cDNA synthesis was carried out by using a Reverse Transcription System kit according to the instructions of the manufacturer (Promega, Madison, WI).…”

Section: Reverse Transcriptase-pcrmentioning

confidence: 99%

Downregulation of SnoN Expression in Obstructive Nephropathy Is Mediated by an Enhanced Ubiquitin-Dependent Degradation

Tan

Zhang²,

Tan³

et al. 2006

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Smad transcriptional co-repressor SnoN acts as an antagonist that tightly controls the trans-activation of TGF-␤/Smad target genes. SnoN protein is reduced progressively in the fibrotic kidney after obstructive injury, suggesting that the loss of Smad antagonist is a critical event that leads to an uncontrolled fibrogenic signaling. However, the mechanism underlying SnoN downregulation remains unknown. This study investigated the regulation and mechanism of renal SnoN expression in vivo. Whereas SnoN protein was markedly diminished, its mRNA levels remained relatively constant in the obstructed kidney after ureteral ligation. An increased ubiquitination and proteasome-dependent degradation of SnoN was found in obstructed kidney, compared with sham controls. Smad ubiquitination regulatory factor-2, an E3 ubiquitin ligase, was induced and formed a complex with SnoN in vivo. In vitro, TGF-␤1 promoted SnoN protein degradation, which was mediated by ubiquitination and a proteasome-dependent mechanism. SnoN constitutively interacted with another Smad co-repressor, Ski, and they formed ternary complex with Smad2/3 upon TGF-␤1 stimulation. However, ectopic expression of Ski did not alter the degradation rate of SnoN. Blockage of SnoN degradation by proteasome inhibitor abolished TGF-␤1-mediated ␣-smooth muscle actin and fibronectin induction, suggesting that SnoN degradation could be necessary for TGF-␤1 to exert its fibrogenic action. Furthermore, knockdown of Smad ubiquitination regulatory factor-2 expression by small interfering RNA strategy led to an increase in SnoN abundance and inhibited the TGF-␤1-mediated gene transcription. These results indicate that downregulation of SnoN expression in the obstructed kidney is mediated by an enhanced ubiquitin-dependent degradation. Preservation of SnoN by inhibiting its degradation may be a novel strategy for targeting hyperactive Smad signaling in renal fibrotic diseases.

“…Calcitriol also alleviates chronic allograft nephropathy in rats by altering TGF-␤1 and matrix-regarding molecules (19). Although most of these studies focused on the effect of calcitriol or one of its analogs on glomerular damage, the suppressive effect of calcitriol on renal interstitial myofibroblasts indicates that calcitriol has a potential role in suppressing the development of renal interstitial fibrosis (20). Recently, Tan et al (21) demonstrated that the vitamin D analog paricalcitol attenuates renal interstitial fibrosis in a mouse model of obstructive nephropathy.…”

mentioning

confidence: 99%

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and a Vitamin D Analog Suppresses the Progression of Renal Insufficiency in Uremic Rats

Mizobuchi¹,

Morrissey²,

Finch³

et al. 2007

184

148

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic ؉ vehicle (UC), uremic ؉ enalapril (30 mg/L in drinking water; E), uremic ؉ paricalcitol (19-nor; 0.8 g/kg, three times a week), and uremic ؉ enalapril ؉ paricalcitol (E ؉ 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E ؉ 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E ؉ 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E ؉ 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E ؉ 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E ؉ 19-nor compared with E group. TGF-␤1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E ؉ 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E ؉ 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-␤ signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.