1,25-Dihydroxyvitamin D3 targeting of NF-κB suppresses high glucose-induced MCP-1 expression in mesangial cells

Zhang, Z.; Yuan, Weiping; Sun, Lin; Szeto, Frances L.; Wong, Kari E.; Li, X.; Kong, Juan; Li, Y.C.

doi:10.1038/sj.ki.5002296

Cited by 169 publications

(144 citation statements)

References 44 publications

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“…Changes in ␣-tropomyosin and in the NF-B pathway, which have been linked with ventricular hypertrophy (31,32), were also positively modified by PC. This is consistent with the finding that 1,25(OH) 2 D 3 significantly blunts the activation of NF-B signaling in vitro (33). Finally, cardiac renin gene expression was attenuated by PC, a finding consistent with Li et al (6,34) (35), and mast cells contain the VDR (36).…”

Section: Discussionsupporting

confidence: 81%

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Bodyak

Ayus²,

Achinger³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

304

250

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Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)2D2), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS؉PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS؉PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials.cardiac hypertrophy ͉ heart failure ͉ paricalcitol ͉ renal failure T he rate of cardiovascular-related mortality in hemodialysis patients is 10-20 times higher than that observed in the general population (1). Left ventricular hypertrophy (LVH) and diastolic dysfunction are present in Ͼ50% of patients at dialysis initiation, and these abnormalities are strongly linked with dialysis-related mortality (2). Currently, there are no well accepted means to modify cardiac structural and functional alterations in renal-failure patients.We recently demonstrated in observational studies that therapy with activated vitamin D to chronic hemodialysis patients is associated with reduction in cardiovascular-related mortality (3, 4). Conversion of nutritional vitamin D (25(OH)D 3 ) to the hormonally active form of vitamin D (1,25(OH) 2 D 3 ) occurs primarily in the kidney; thus, patients with kidney failure commonly present with altered vitamin D status (5). There is growing evidence that vitamin D either directly or indirectly affects cardiac structure and function. The vitamin D receptor knockout mouse model demonstrates increased cardiac renin expression and marked cardiomyocyte hypertrophy (6), and 1,25(OH) 2 D 3 attenuates cardiomyocyte proliferation (7) and hypertrophy (8) in vitro. Here, we demonstrate that treatment with an activated vitamin D compound attenuates the development of cardiac hypertrophy and dysfunction in a recognized animal model of such abnormalities and that comparable findings are evident in humans.

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Section: Discussionsupporting

confidence: 81%

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Bodyak

Ayus²,

Achinger³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

304

250

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“…Monocyte/macrophage infiltration into the kidney, stimulated by MCP-1 produced from kidney cells in diabetic state, promotes kidney fibrosis and renal injury through secretion of inflammatory cytokines. Although vitamin D alone can directly suppress the high-glucose induction of TGF-␤ and MCP-1 in mesangial cells (50), this study showed that cotreatment with losartan and paricalcitol achieved better inhibition of these cytokines in vivo. Because TGF-␤ and MCP-1 are up-regulated by Ang II, the suppression of these factors by the cotreatment is likely mediated by the blockade of Ang II accumulation (Fig.…”

Section: Discussionmentioning

confidence: 95%

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

225

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The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We albuminuria ͉ glomerulosclerosis ͉ renin-angiotensin system D iabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease and high mortality (1). Previous studies have suggested the renin-angiotensin system (RAS) as a major mediator of progressive renal injury in diabetic nephropathy. Drugs targeting the RAS including angiotensin (Ang)-converting enzyme inhibitors (ACEIs) and Ang II type 1 receptor blockers (ARBs) have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (2-6). The systemic components of the RAS are actually down-regulated in diabetic mellitus (7), whereas renal interstitial Ang II levels are estimated to be 1,000-fold higher than in the plasma (8); therefore, intrarenal RAS is thought to play the major damaging role. In fact, all components of the RAS are present within the kidney (9). Cells in the kidney are able to synthesize renin, prorenin/renin receptor (10), angiotensinogen, and Ang II receptors independent of the systemic RAS (11), making the kidney capable of maintaining a high level of intrarenal Ang II. Intrarenal renin and angiotensinogen levels are induced in diabetic animals (12, 13), and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes (14-16). Intrarenal Ang II exerts multiple effects on the kidney that promote the progression of renal injury; these include an increase in glomerular capillary pressure, induction of profibrotic and proinflammatory cytokine production, promotion of immune cell infiltration, stimulation of cell proliferation and hypertrophy, up-regulation of extracellular matrix (ECM) synthesis, and damaging of podocytes (17)(18)(19) (21), and null mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy (22)(23)(24). Our recent studies showed that in diabetic state VDR-null mice developed more severe nephropathy than wild-type mice (25), suggesting that vitamin D plays a protective role against hyperglycemia-induced renal injury by regulation of the RAS. However, whether vitamin D or vitamin D analogs have therapeutic effects in intervention or prevention of diabetic nephropathy remains to be tested.Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the...

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“…High glucose, for instance, stimulates MCP1 gene expression by activating AP1 (5), or protein kinase C (PKC) and NF-kB (6), in peritoneal mesothelial cells. High glucose also increases MCP1 mRNA levels in renal mesangial cells through NF-kB activation (7), which provides insight into understanding the development of diabetic nephropathy. In renal proximal tubular cells, albumin induces MCP1 expression by producing reactive oxygen species and, in turn, activating NF-kB when the cells are treated with an excess of albumin (8).…”

mentioning

confidence: 99%

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

Kojima

Taniguchi

Tsuzuki

et al. 2010

The Journal of Immunology

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MCP1 is upregulated by various stimuli, including LPS, high glucose, and hyperosmolality. However, the molecular mechanisms of transcriptional regulation of the MCP1 gene under hyperosmolar conditions are poorly understood. Treatment of NRK52E cells with NaCl or mannitol resulted in significant elevation of MCP1 mRNA and protein in a time- and dose-dependent manner. Treatment with a p38MAPK inhibitor (SB203580), an ERK inhibitor (PD98059), or an MEK inhibitor (U0126), suppressed the increase in MCP1 expression caused by hypertonic NaCl, whereas a JNK inhibitor (SP600125) and an AP1 inhibitor (curcumin) failed to attenuate MCP1 mRNA expression by NaCl. In the 5′-flanking region of the MCP1 gene, there is a sequence motif similar to the consensus TonE/ORE as well as the consensus C/E binding protein (BP), NF-κB, and AP1/Sp1 sites. Luciferase activity in cells transfected with reporter constructs containing a putative TonE/ORE element (MCP1-TonE/ORE) enhanced reporter gene expression under hypertonic stress. Results of electrophoretic gel mobility shift assay showed a slow migration of the MCP1-TonE/ORE probe, representing the binding of TonEBP/OREBP/NFAT5 to this enhancer element. These results indicate that the 5′-flanking region of MCP1 contains a hypertonicity-sensitive cis-acting element, MCP1-TonE/ORE, as a novel element in the MCP1 gene. Furthermore, p38MAPK and MEK–ERK pathways appear to be, at least in part, involved in hypertonic stress-mediated regulation of MCP1 expression through the MCP1-TonE/ORE.

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1,25-Dihydroxyvitamin D3 targeting of NF-κB suppresses high glucose-induced MCP-1 expression in mesangial cells

Cited by 169 publications

References 44 publications

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

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