Paricalcitol Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy

Tan, Xiaoyue; Li, Yingjian; Liu, Youhua

doi:10.1681/asn.2006050520

Cited by 263 publications

(272 citation statements)

References 49 publications

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“…Consistent with a previous report, 10 obstructive injury caused a suppression of VDR, and paricalcitol largely restored VDR expression after UUO ( Figure 10B). Interestingly, immunostaining exhibited that a large proportion of VDR was localized in the nuclei in normal kidney (Figure 10C), suggesting an active role of the vitamin D system in the maintenance of normal tubular integrity.…”

Section: Paricalcitol Does Not Affect Nf-b Nuclear Translocation But supporting

confidence: 93%

“…[3][4][5] Evidence is also mounting that vitamin D analogue is renoprotective in different experimental nephropathies. 6 Although early studies largely focused on primary glomerular diseases, [7][8][9] active vitamin D was shown to display beneficial effects in obstructive nephropathy, 10 a model characterized by inflammatory infiltration, tubular atrophy, and interstitial fibrosis. The therapeutic effects of active vitamin D in obstructive nephropathy are thought to be mediated by its ability to preserve tubular epithelial integrity via inhibiting epithelial-to-mesenchymal transition (EMT) 10 ; however, in view of its pleiotropic property, it is conceivable that vitamin D could elicit its renoprotection by a multitude of actions.…”

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confidence: 99%

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

Tan

Wen

Liu

2008

Journal of the American Society of Nephrology

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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.

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Section: Paricalcitol Does Not Affect Nf-b Nuclear Translocation But supporting

confidence: 93%

mentioning

confidence: 99%

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

Tan

Wen

Liu

2008

Journal of the American Society of Nephrology

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243

199

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“…As aberrant expression of TGF-b1 has been revealed in virtually all CKD patients, an inhibitor for the TGF-b1/Smad signaling pathway seems to be a promising agent. 14 Although Tan et al 23,25 reported that another lesscalcemic analog, paricalcitol, suppresses both renal renin and TGF-b1 levels in UUO mice, the mechanism how paricalcitol suppresses TGF-b1 is currently unknown. Because the activation of RAS can induce TGF-b1 expression, TGF-b1-suppressive effect of paricalcitol might be derived merely from the suppression of RAS.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate tubular injury and interstitial volume, we performed morphometric analyses in PAS-stained sections. 23 Briefly, digital images of cortical high-power magnification ( Â 400) were taken by BZ-9000 microscopy (KEYENCE, Osaka, Japan). Then, a grid that contained 120 (12 Â 10) sampling points was superimposed on the images.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

Inoue

Matsui

Hamano

et al. 2012

Laboratory Investigation

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Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-b1 (TGF-b1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-b1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-b1, pSmad3 bound to the proximal promoter region of the TGF-b1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-b1 increased both the nuclear levels of protein phosphatase Mg 2 þ /Mn 2 þ -dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-b1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-b1. Our findings provide a novel approach to inhibit the TGF-b pathway in fibrotic diseases. Tubulointerstitial fibrosis (TIF) is the final common pathway for most forms of progressive kidney diseases. 1-3 Numerous studies revealed that two major signaling pathways, the renin-angiotensin system (RAS) and the transforming growth factor-b1 (TGF-b1)/Smad system, have important roles in the pathogenesis of TIF. [3][4][5][6] However, because satisfactory therapeutic strategies have not been established, TIF remains one of the major problems in nephrology.One of the candidates that protect the kidney from TIF is active vitamin D because it is a negative regulator of renin. 7,8 Several lines of studies revealed the renin-suppressive effect of 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. [9][10][11][12] In addition to 1,25(OH) 2 D, a less-calcemic analog, paricalcitol, has been revealed to suppress renin in the kidney. 13 These findings provide a rationale for active vitamin D therapy in renal diseases with high local renin.

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“…[7][8][9] Vitamin D has been linked with important anti-inflammatory and immunomodulatory roles where it regulates cytokines and profibrotic and pro-inflammatory pathways that play an important role in pain perception and propagation. [10][11][12][13][14][15] Clinically, vitamin D deficiency has been associated with chronic non-specific musculoskeletal pain syndromes and migraines. [16][17][18] Vitamin D deficient individuals have reported pain even in the absence of actual bone pathology.…”

Section: Résumémentioning

confidence: 99%

Low serum vitamin D levels are not associated with increased postoperative pain and opioid requirements: a historical cohort study

Bose

Khanna

You

et al. 2015

Can J Anesth/J Can Anesth

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Purpose Vitamin D deficiency has been associated with chronic non-specific musculoskeletal pain syndromes; however, studies are lacking with respect to its relationship with postoperative pain. We tested the hypothesis that a lower preoperative vitamin D level is associated with increased postoperative pain and/or opioid consumption in morbidly obese patients who had laparoscopic bariatric surgery.

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Paricalcitol Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy

Cited by 263 publications

References 49 publications

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

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

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

Low serum vitamin D levels are not associated with increased postoperative pain and opioid requirements: a historical cohort study

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