Multiple facets of macrophages in renal injury

Kluth, David; Erwig, Lars P.; Rees, Andrew J.

doi:10.1111/j.1523-1755.2004.00773.x

Cited by 131 publications

(109 citation statements)

References 174 publications

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“…34 The role of CCL2/MCP1, 22,23 CCL5/RANTES, 22 and CCL7/MCP3 24 is clearly established in this process. Our data show reduced renal expression of these three chemokines in response to B1Ra treatment in the NTS model.…”

Section: Discussionmentioning

confidence: 99%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, HenochSchö nlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis. Rapidly progressive glomerulonephritides constitute a group of kidney diseases sharing common pathologic features. These nephropathies are characterized by severe glomerular inflammation, mainly composed of infiltrating macrophages and T cells. This leads to the formation of glomerular crescents composed of immune and proliferating epithelial cells from the Bowman's capsule. After the primary glomerular insult, inflammation and lesions extend to the tubulointerstitial compartment and induce tubular damage and progressive interstitial fibrosis, leading to the loss of renal function; therefore, renal inflammation is a key player in the initiation and the progression of these pathologies. It has been suggested that any strategy or agent able to limit or attenuate renal inflammation should significantly slow the progression of glomerulonephritides to ESRD. 1 Endogenous kinins (bradykinin-related peptides)are produced through cleavage of kininogens by kallikreins. These peptides mediate their biologic effects by activation of two G protein-coupled receptors: a constitutively expressed B2 receptor (B2R) and an inducible B1 receptor (B1R). 2 Bradykinin and kallidin are the natural agonists of the B2R, whereas their metabolites, generated by the enzyme kininase I, desArg9-BK and Lys-des-Arg9-BK, respectively, are spe-

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Section: Discussionmentioning

confidence: 99%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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“…Firstly, Midkine in tubulointerstitial damage T Kosugi et al studies involving human biopsy specimens and animal models have revealed that macrophage infiltration is a characteristic of diabetic nephropathy. [26][27][28][29][30] Secondly, mice deficient in MCP-1 or ICAM-1 exhibit a marked reduction of nephropathy in the type I diabetes model with STZ. 4,6 MCP-1 or ICAM-1 deficiency also prevent nephropathy in type II diabetic db/db mice.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25][26] Thus, selectins on inflammatory cells or endothelial cells bind to their ligands, and then induce the tethering and rolling of inflammatory cells on endothelial cells. Chemokines such as MCP-1 on the endothelium are recognized by their receptors on inflammatory cells, 25 and then activate integrins.…”

Section: Discussionmentioning

confidence: 99%

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

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The concept that inflammation plays a crucial role in the pathogenesis of diabetic nephropathy has been recently emerging, although the principal pathology of diabetic nephropathy comprises glomerular sclerosis and associated changes in nephrons. Here, we identified the growth factor midkine (MK) as a novel key molecule involved in inflammation associated with Streptozotocin-induced diabetic nephropathy. The tubulointerstitial damage, as assessed as morphological changes, osteopontin expression, collagen I deposition and macrophage infiltration, were strikingly less in MK-deficient (Mdk À/À ) mice than in Mdk þ / þ mice. Monocyte chemoattractant protein (MCP)-1 expression, but not that of intercellular adhesion molecule-1, was also lower in Mdk À/À mice. High glucose upregulated MK expression in primarycultured tubular epithelial cells, and induced MCP-1 to a larger extent in Mdk þ / þ cells than in Mdk À/À cells. Correspondingly, the combination of exogenous MK and high glucose enhanced MCP-1 expression in Mdk À/À cells. Furthermore, high glucose and oxidant stress enhanced MK expression in macrophages. Consistent with the findings in the mouse model, MK expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy. Our data indicate that MK plays a critical role in the tubulointerstitial inflammation associated with diabetic nephropathy through activation of the MCP-1 pathway.

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“…Infiltrating T cells can induce tissue injury, either directly by cytotoxic functions and cytokine secretion or indirectly by activating macrophages. 1,2 In particular, infiltrating effector T cells of the Th1 type are supposed to initiate and perpetuate renal tissue damage in crescentic and proliferative forms of glomerulonephritis, which eventually leads to progressive loss of renal function. 3 This pathophysiological concept is mainly based on findings from experimental rodent models of glomerulonephritis.…”

Section: Il-17mentioning

confidence: 99%