Inflammatory mediators and growth factors in obstructive renal injury

Misseri, Rosalia; Rink, Richard C.; Meldrum, Daniel R.; Meldrum, Kirstan K.

doi:10.1016/j.jss.2004.02.016

Cited by 76 publications

(55 citation statements)

References 108 publications

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“…1,6 The mechansim(s) by which suramin reduces inflammation is currently not clear. However, our data indicate that suramin treatment is also able to suppress expression of multiple cytokines (including TNF␣, IL-␤1, and ICAM-1) and leukocyte infiltration, 22 suggesting that inhibition of the inflammatory response is also one of the mechanisms by which suramin attenuates renal fibrosis.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

“…3,4 Although the mechanism of myofibroblast activation and the fibrogenesis under various pathologic conditions have not been completely understood, activation of multiple cytokines/growth factor receptors is involved in these processes. [5][6][7] Injury to the kidney is associated with release of cytokines/growth factors such as TGF-␤, EGF, and PDGF by damaged or infiltrating cells. 5,8,9 An increase in production of TGF-␤ is one of the most important mechanisms in the pathogenesis of renal fibrogenesis.…”

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confidence: 99%

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Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Liu

Tolbert

Pang

et al. 2011

Journal of the American Society of Nephrology

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The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and growth factors with their receptors, but whether suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with suramin inhibited their activation induced by TGF-␤1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of ␣-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-␤1 and reduced the interstitial infiltration of leukocytes. Moreover, suramin decreased expression of the type II TGF-␤ receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.

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Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

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confidence: 99%

Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Liu

Tolbert

Pang

et al. 2011

Journal of the American Society of Nephrology

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“…*P Ͻ 0.05 compared with sham (Sh)-operated group; ‡P Ͻ 0.05 compared with corresponding WT group. ney such as tubular dilation, apoptotic tubular cell deletion, and fibrosis, 38 tubulointerstitial injury occurs in a wide variety of diseases including diabetic nephropathy, chronic allograft nephropathy, and inflammatory kidney diseases. Tubulointerstitial inflammation and fibrosis are important prognostic markers of an adverse outcome in patients with a wide variety of kidney diseases.…”

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

112

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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“…The histological derangements associated with obstruction are localized primarily to the tubulointerstitial compartment of the kidney and include massive tubular dilation, apoptotic tubular cell deletion, and progressive tubulointerstitial fibrosis (28,30). Initially, changes in renal function are reversible; however, with sustained injury, these histological alterations translate into a permanent loss in renal function.…”

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confidence: 99%