Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Eis, Václav; Luckow, Bruno; Vielhauer, Volker; Siveke, Jens T.; Linde, Yvonne; Segerer, Stephan; Lema, Guillermo Pérez de; Cohen, Clemens D.; Kretzler, Matthias; Mack, Matthias; Horuk, Richard; Murphy, Philip M.; Gao, Ji; Hudkins, Kelly L.; Alpers, Charles E.; Gröne, Hermann Josef; Schlöndorff, Detlef; Anders, Hans‐Joachim

doi:10.1097/01.asn.0000111246.87175.32

Cited by 121 publications

(99 citation statements)

References 33 publications

(41 reference statements)

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“…Th2 cell-produced IL-4 and IL-13 are critical mediators of renal fibrosis. Advanced renal fibrosis in patients with CKD, 17 as well as in animal models of renal fibrosis (including UUO), [18][19][20] is invariably associated with tubulointerstitial infiltration of T lymphocytes. Recently, the pivotal role of CD4 + T cells in the progression of renal fibrosis was discovered using severe combined immunodeficient mice and a depleting anti-CD4 antibody.…”

Section: Discussionmentioning

confidence: 99%

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Ito

Yan

Nagata

et al. 2012

Journal of the American Society of Nephrology

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Urinary excretion of lipocalin-type PGD 2 synthase (L-PGDS), which converts PG H 2 to PGD 2 , increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD 2 contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD 2 might be a strategy to slow the progression of renal fibrosis in CKD.

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Section: Discussionmentioning

confidence: 99%

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Ito

Yan

Nagata

et al. 2012

Journal of the American Society of Nephrology

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“…This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

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“…Likewise, cross-linking of myeloid IgA Fc receptors (Fc␣RI or CD89) aggravates IgA nephropathy and anti-GBM nephritis in an FcR␥-dependent manner (10). Macrophages and T cells are important in the inflammation associated with ureteral obstruction, another common cause of ESRD (11)(12)(13)(14)(15)(16). Conventional antiinflammatory therapy for ESRD, based on steroids, immunosuppressants, and angiotensin-converting enzyme inhibitors have limited efficacy on disease progression (17).…”

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confidence: 99%

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Kanamaru

Pfirsch

Aloulou

et al. 2008

The Journal of Immunology

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Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcαRI-Fcγ ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcαRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

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Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Cited by 121 publications

References 33 publications

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Complement activation in progressive renal disease

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

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