TNF-α neutralization ameliorates obstruction-induced renal fibrosis and dysfunction

Meldrum, Kirstan K.; Misseri, Rosalia; Metcalfe, Peter; Dinarello, Charles A.; Hile, Karen L.; Meldrum, Daniel R.

doi:10.1152/ajpregu.00620.2005

Cited by 91 publications

(79 citation statements)

References 39 publications

(64 reference statements)

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“…Moreover, TNFa can inhibit VDR expression while enhancing the ability of TGFb1 to stimulate EMT in breast cancer cells, as determined by the induction of a-SMA and the loss of E-cadherin. This is in accord with previous research from our group and others which has identified both the inhibitory effect of TNFa on VDR expression in different cell lines and the synergistic effect of TNFa and TGFb1 on EMT induction (14,27,28).…”

Section: Discussionsupporting

confidence: 93%

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Zhang¹,

Guo²,

Zhang

et al. 2014

Molecular Cancer Research

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The relationship between tumor-associated macrophages (TAM) and epithelial-to-mesenchymal transition (EMT) during the initiation and progression of metastasis is still unclear. Here, a role for the vitamin D receptor (VDR) in metastasis was identified, as well as a role in the relationship between TAMs and EMT. First, the expression level of VDR was examined in clinical tissue from human patients with breast cancer or a mouse model of breast cancer with differential metastasis. These results revealed that VDR expression negatively correlates with metastasis in breast cancer. Second, coculture of VDR-overexpressing breast cancer cells with a macrophage cell line demonstrated that overexpression of VDR alleviated the prometastatic effect of cocultured macrophages on breast cancer cells. Furthermore, VDR overexpression abrogated the induction of EMT in breast cancer cells by cocultured macrophage cells, as measured by a loss of E-cadherin (CDH1) and induction of a-smooth muscle actin (a-SMA). TNFa in macrophage conditioned media inhibited VDR expression, whereas downregulation of VDR further mediated the promotion of TGFb-induced EMT by TNFa. In addition, b-catenin expression was inhibited in VDR-overexpressing breast cancer cells and tumor xenografts.

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Section: Discussionsupporting

confidence: 93%

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Zhang¹,

Guo²,

Zhang

et al. 2014

Molecular Cancer Research

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“…This is consistent with previous reports linking inflammatory infiltration to cytokine release, ECM imbalance, and fibrosis. 2,47,48 TNF␣ plays an important role in mediating renal fibrosis and dysfunction in response to UUO 31,33 and chemotherapy-induced nephropathy. 49 TNF␣-induced injury is mediated via both its receptors, TNFR1 and TNFR2, with clear evidence for a proapoptotic role in renal tissue.…”

Section: Increased Timp3 Levels In Human Kidney Diseasementioning

confidence: 99%

Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

Kassiri¹,

Oudit²,

Kandalam³

et al. 2009

Journal of the American Society of Nephrology

114

127

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The balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) determines the integrity of the extracellular matrix. TIMP3 is the most highly expressed tissue inhibitor of metalloproteinase (TIMP) in the kidney, but its function in renal disease is incompletely understood. In this study, TIMP3 Ϫ/Ϫ mice demonstrated an age-dependent chronic tubulointerstitial fibrosis. After unilateral ureteral obstruction (UUO), young TIMP3 Ϫ/Ϫ mice exhibited increased renal injury (tubular atrophy, cortical and medullary thinning, and vascular damage) compared with wild-type mice. In addition, TIMP3 Ϫ/Ϫ mice had greater interstitial fibrosis; increased synthesis and deposition of type I collagen; increased activation of fibroblasts; enhanced apoptosis; and greater activation of MMP2, but not MMP9, after UUO. TIMP3 deficiency also led to accelerated processing of TNF␣, demonstrated by significantly higher TACE activity and greater soluble TNF␣ levels by 3 d after UUO. The additional deletion of TNF␣ markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3 Ϫ/Ϫ /TNF␣ Ϫ/Ϫ mice further abrogated postobstructive injury and prevented tubulointerestitial fibrosis. In humans, TIMP3 expression increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy. Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease.

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“…Thus, it is reasonable to speculate that infiltrating mononuclear phagocytes in obstructed kidney play a pivotal role in eliciting tubular apoptosis by stimulating expression of TNF-α and/or TGF-β. TNF-α neutralization also ameliorates obstruction-induced renal fibrosis (26). TGF-β is highly correlated to the fibrogenic process, directly stimulates production of extracellular matrix and myofibroblast transdifferentiation, and plays a central role in renal fibrosis (27).…”

Section: Depleted F4/ 80mentioning

confidence: 99%

Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy

et al. 2009

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Abstract. Although liposome-encapsulated clodronate has been used as a means to deplete macrophages from certain tissues, target leukocyte subtypes within the kidney are not clearly known under normal and pathologic conditions. The present study was therefore conducted to examine the effects of liposome clodronate on renal infiltrating cell type following unilateral ureteral obstruction (UUO) and tried to correlate these changes to the mechanisms of early development of renal fibrosis. Renal infiltrating leukocyte subtypes and counts were determined by using multicolor flow cytometric analysis of cell suspensions from obstructed kidneys. UUO for 5 days elicited renal tubular apoptosis and renal fibrosis and showed 4-fold increase in renal leukocytes including monocytes/macrophages, dendritic cells, and T-cells. Repeated administration of liposome clodronate selectively depleted F4/80 + monocytes /macrophages and F4/80 + dendritic cells but not F4/80 − dendritic cells or other cell types in both obstructed and nonobstructed kidneys. Tubular apoptosis and renal fibrosis were also significantly attenuated by liposome clodronate. Increased gene expression of TNF-α and TGF-β observed in obstructed kidneys were markedly attenuated by depletion of renal mononuclear phagocytes. These findings suggest that F4/80 + monocytes /macrophages and/or F4/80 + dendritic cells play a pivotal role in the development of obstruction-induced tubular apoptosis and renal fibrosis, possibly through TNF-α and TGF-β dependent mechanisms.

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TNF-α neutralization ameliorates obstruction-induced renal fibrosis and dysfunction

Abstract: Meldrum KK, Misseri R, Metcalfe P, Dinarello CA, Hile KL, Meldrum DR. TNF-␣ neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.

Cited by 91 publications

References 39 publications

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy

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