Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis

Panzer, Ulf; Thaiss, Friedrich; Zahner, Gunther; Barth, Petra; Reszka, Mariola; Reinking, Rolf R.; Wolf, Günter; Helmchen, Udo; Stahl, Rolf A.K.

doi:10.1046/j.1523-1755.2001.0590051762.x

Cited by 100 publications

(82 citation statements)

References 28 publications

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“…Earlier studies demonstrated that the expression of OPN correlates well with macrophage infiltration in various experimental models of renal injury. 42, 43 Persy et al 44 showed that the loss of OPN expression in OPN-deficient mice resulted in a significant reduction in macrophage infiltration and renal fibrosis in a murine model of ischemia reperfusion injury. In our current study, reduction of macrophage infiltration in UUO following MMP-9 inhibition was associated with a reduction in expression of MMP-cleaved OPN corresponding to the protein size of 32 kDa and not the expression of chemokine CCL-2, which was previously found to be a key macrophage chemoattractant in UUO model.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

132

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

132

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“…118,119 In addition, through thrombospondin 1, Ang II activates the release of active TGF␤ from the latent complex. 118,119 Finally, Ang II directly upregulates type 2 TGF␤ receptors by mediating transcriptional activity of the receptor gene. 36 tiation from tubular cells to macula densa cells can be controlled by angiotensin type 2 receptors (AT2Rs).…”

Section: Ang II and Epithelial-mesenchymal Transitionmentioning

confidence: 99%

“…118,119 In several models of kidney fibrosis with increases in local Ang II, endothelin simultaneously increases endothelin-1 (ET-1). 85,89 In a model of severe Ang II-dependent hypertension in Ren-2 transgenic rats, the role of Ang II, ET-1, and L-type calcium channels in the development of glomerular, vascular, and tubulointerstitial fibrosis is observed after treatment with irbesartan, bosentan, and a selective endothelin receptor antagonist.…”

Section: Ang II and Other Profibrotic Factorsmentioning

confidence: 99%

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Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Rüster

Wolf

2011

Journal of the American Society of Nephrology

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175

150

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Chronic kidney disease (CKD) is increasing worldwide. Although the cause of its progression is multifactorial, 1-3 activation of the renin-angiotensin-aldosterone system (RAAS) is a key effector and RAAS inhibitors are among the beststudied renoprotective agents. 4 -7 Although the RAAS is complex, with new peptides such as angiotensin 1-7 and angiotensin IV exhibiting profibrotic effects by binding to specific receptors as well as observations that aldosterone and even renin itself can stimulate fibrogenesis in the kidney, 8 -12 and angiotensin II (Ang II) blockade can stimulate renin release, 13 the review presented here focuses exclusively on Ang II as the major component of the RAAS effect on morphogenesis. There are several excellent reviews covering the other components of the RAAS and their profibrotic actions in the kidney. 8 -10,14 The classic view of Ang II as a vasoactive agent involved in local and systemic hemodynamic regulation 15 needs extension to encompass its properties as a morphogenic cytokine with an active role in renal pathology. 16,17 Ang II was first described 2 decades ago as stimulating the hypertrophy of tubular cells and the associated increase in collagen secretion. 18,19 Fibrosis is the final common pathway leading to renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. 20 -22 Ang II modulates renal cell growth and extracellular matrix (ECM) synthesis or degradation. 17,[23][24][25] For example, overexpression of renin and angiotensinogen in rat glomeruli leads to expanded ECM without inducing systemic hypertension. 26,27 The stimulatory effects of Ang II on increased collagen expression depend on various mechanisms. In addition to angiotensin-converting enzyme (ACE), which is the most well known enzyme capable of Ang II formation, other non-ACE Ang II-generating pathways are currently under study. 28 ACE inhibitors also diminish cellular infiltrates and inflammatory markers in many models of renal injury. 29 ANG II AND TGF␤The interactions between Ang II and the TGF␤ axis are multiple and complex (Figure 1). 29 -31 TGF␤ is a fibrogenic and anti-inflammatory cytokine and plays a critical role in the pathophysiology of renal injury. 32,33 Ang II stimulates transcription and synthesis of TGF␤, particularly TGF␤1, in cultured murine proximal tubular cells and also upregulates specific receptors for TGF␤, further enhancing its profibrogenic action. 34 -36 Ang II directly stimulates complex interactions in the ABSTRACTInhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGF␤. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction...

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“…Therefore, we propose that GM-CSF released by renal parenchymal cells increases the numbers of activated macrophages that are capable of releasing further inflammatory mediators (e.g., IL-1␤), previously demonstrated to be critical in the progression of GN (29). Mesangial cells produce MCP-1 in response to IL-1␤ (53); furthermore, blocking MCP-1 via Ab reduces glomerular injury and proteinuria (54,55). Hence, renal GM-CSF may regulate glomerular and tubular injury through MCP-1 by influencing IL-1␤ or in an autocrine feedback loop as renal cells have been demonstrated to be the principal producers of MCP-1 (56).…”

Section: Discussionmentioning

confidence: 91%

Granulocyte Macrophage Colony-Stimulating Factor Expression by Both Renal Parenchymal and Immune Cells Mediates Murine Crescentic Glomerulonephritis

Timoshanko

Kitching

Semple

et al. 2005

Journal of the American Society of Nephrology

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Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis

Cited by 100 publications

References 28 publications

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Granulocyte Macrophage Colony-Stimulating Factor Expression by Both Renal Parenchymal and Immune Cells Mediates Murine Crescentic Glomerulonephritis

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