Complement Regulation in Renal Disease Models

Naik, Abhijit S.; Sharma, Shweta; Quigg, Richard J.

doi:10.1016/j.semnephrol.2013.08.008

Cited by 27 publications

(23 citation statements)

References 94 publications

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“…Inherited and acquired abnormalities of membrane cofactor protein, a complement regulator present in the renal TI [2], [30] can underlie atypical hemolytic uremic syndrome and acute kidney injury, respectively [8]. Given their similar distributions and shared functions, our findings with Crry in the kidney are relevant to these human disease states in which there is abnormal complement regulation by membrane cofactor protein [31].…”

Section: Discussionmentioning

confidence: 73%

Loss of CD11b Exacerbates Murine Complement-Mediated Tubulointerstitial Nephritis

et al. 2014

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Acute complement activation occurs in the tubulointerstitium (TI) of kidneys transplanted from Crry−/−C3−/− mice into complement-sufficient wildtype mice, followed by marked inflammatory cell infiltration, tubular damage and interstitial fibrosis. We postulated iC3b-CD11b interactions were critical in this TI nephritis model. We transplanted Crry−/−C3−/− mouse kidneys into CD11b−/− and wildtype C57BL/6 mice. Surprisingly, there was greater inflammation in Crry−/−C3−/− kidneys in CD11b−/− recipients compared to those in wildtype hosts. Kidneys in CD11b−/− recipients had large numbers of CD11b−Ly6ChiCCR2hiF4/80+ cells consistent with inflammatory (M1) macrophages recruited from circulating monocytes of the host CD11b−/− animal. There was also an expanded population of CD11b+CD11c+Ly6C−F4/80hi cells. Since these cells were CD11b+, they must have originated from the transplanted kidney; their surface protein expression and appearance within the kidney were consistent with the intrinsic renal mononuclear cellular population. These cells were markedly expanded relative to all relevant controls, including the contralateral donor kidney and Crry−/−C3−/− mouse kidneys in CD11b+/+ wildtype recipients. Direct evidence for their in situ proliferation was the presence of nuclear Ki67 and PCNA in CD11b+F4/80+ cells. Thus, in this experimental model in which there is unrestricted C3 activation, CD11b+ monocytes limit their own infiltration into the kidney and prevent proliferation of endogenous mononuclear cells. This suggests a role for outside-in iC3b-CD11b signals in limiting intrinsic organ inflammation.

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Section: Discussionmentioning

confidence: 73%

Loss of CD11b Exacerbates Murine Complement-Mediated Tubulointerstitial Nephritis

et al. 2014

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“…Several animal studies have demonstrated a beneficial effect of blocking the alternative C pathway in LN (84). Although little work has been done with C inhibition in human LN, effective inhibitors are available, including a monoclonal antibody against C5 (eculizumab) and a small molecule C5a receptor blocker (CCX168) (85).…”

Section: Controlling Renal Inflammation In Lnmentioning

confidence: 99%

Update on Lupus Nephritis

Almaani

Meara

Rovin

2016

CJASN

708

535

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SLE is a chronic inflammatory disease that affects the kidneys in about 50% of patients. Lupus nephritis is a major risk factor for overall morbidity and mortality in SLE, and despite potent anti-inflammatory and immunosuppressive therapies still ends in CKD or ESRD for too many patients. This review highlights recent updates in our understanding of disease epidemiology, genetics, pathogenesis, and treatment in an effort to establish a framework for lupus nephritis management that is patient-specific and oriented toward maintaining long-term kidney function in patients with lupus.

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“…In contrast to widespread expression in humans, in mice and rats the CD46 molecule is exclusively expressed in testis. Mice and rats also have complement receptor 1-related gene protein y (Crry) that regulates C3 activation and has CD46 and CD55 like activity (Naik et al, 2013). …”

Section: Complement System and Normal Pregnancymentioning

confidence: 99%

The complement system and adverse pregnancy outcomes

Regal

Gilbert

Burwick

2015

Molecular Immunology

135

115

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Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the feta allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.

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Complement Regulation in Renal Disease Models

Cited by 27 publications

References 94 publications

Loss of CD11b Exacerbates Murine Complement-Mediated Tubulointerstitial Nephritis

Loss of CD11b Exacerbates Murine Complement-Mediated Tubulointerstitial Nephritis

Update on Lupus Nephritis

The complement system and adverse pregnancy outcomes

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