Renal macrophage infiltration is associated with a poor outcome in IgA nephropathy

Silva, Gyl Eanes Barros; Costa, R. S.; Ravinal, Roberto Cuan; Ramalho, Leandra Náira Zambelli; Reis, Marlene Antônia dos; Moysés-Neto, Miguel; Romão, Elen Almeida; Coimbra, Terezila Machado; Dantas, Márcio

doi:10.6061/clinics/2012(07)01

Cited by 31 publications

(31 citation statements)

References 28 publications

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“…Importantly, in both patients [4], [5], [8] and animal models [7], [9], [10], ROS have been shown to be involved in the progressive stage of IgAN, the most common type of primary glomerulonephritis. In addition, mononuclear leukocyte infiltration in the kidney of IgAN patients is highly implicated in converting IgAN into progressive renal injury [11]–[13]. These inflammatory mediators and pathways are considered a key step in IgAN prior to the development of chronic renal failure [11], [12], [14], [15].…”

Section: Introductionmentioning

confidence: 99%

Osthole Mitigates Progressive IgA Nephropathy by Inhibiting Reactive Oxygen Species Generation and NF-κB/NLRP3 Pathway

et al. 2013

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Renal reactive oxygen species (ROS) and mononuclear leukocyte infiltration are involved in the progressive stage (exacerbation) of IgA nephropathy (IgAN), which is characterized by glomerular proliferation and renal inflammation. The identification of the mechanism responsible for this critical stage of IgAN and the development of a therapeutic strategy remain a challenge. Osthole is a pure compound isolated from Cnidiummonnieri (L.) Cusson seeds, which are used as a traditional Chinese medicine, and is anti-inflammatory, anti-apoptotic, and anti-fibrotic both in vitro and in vivo. Recently, we showed that osthole acts as an anti-inflammatory agent by reducing nuclear factor-kappa B (NF-κB) activation in and ROS release by activated macrophages. In this study, we examined whether osthole could prevent the progression of IgAN using a progressive IgAN (Prg-IgAN) model in mice. Our results showed that osthole administration resulted in prevention of albuminuria, improved renal function, and blocking of renal progressive lesions, including glomerular proliferation, glomerular sclerosis, and periglomerular mononuclear leukocyte infiltration. These findings were associated with (1) reduced renal superoxide anion levels and increased Nrf2 nuclear translocation, (2) inhibited renal activation of NF-κB and the NLRP3 inflammasome, (3) decreased renal MCP-1 expression and mononuclear leukocyte infiltration, (4) inhibited ROS production and NLRP3 inflammasome activation in cultured, activated macrophages, and (5) inhibited ROS production and MCP-1 protein levels in cultured, activated mesangial cells. The results suggest that osthole exerts its reno-protective effects on the progression of IgAN by inhibiting ROS production and activation of NF-κB and the NLRP3 inflammasome in the kidney. Our data also confirm that ROS generation and activation of NF-κB and the NLRP3 inflammasome are crucial mechanistic events involved in the progression of the renal disorder.

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Section: Introductionmentioning

confidence: 99%

Osthole Mitigates Progressive IgA Nephropathy by Inhibiting Reactive Oxygen Species Generation and NF-κB/NLRP3 Pathway

et al. 2013

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“…IgA nephropathy (IgAN) is the most common primary glomerulonephritis and characterized by various degrees of intrinsic cell proliferation, especially mesangial cells (MCs), in the affected glomerulus, and mononuclear leukocyte infiltration in the glomerulus and renal interstitium1234, with insidious progression to end-stage renal disease in up to 50% of the patients56. Deposition of predominantly glomerular IgA immune complexes (ICs) or IgA immune aggregates167, and activation of innate immunity, followed by T cell activation and resultant inflammatory responses have been considered as a leading cause of the disease378.…”

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confidence: 99%

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

Tsai

Hua

Chen

et al. 2017

Sci Rep

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We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.

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“…1 Kruskal-Wallis test: P < 0.0008 biopsies the receptor for the chemokine RANTES (CCRR5) was expressed by interstitial but not by glomerular macrophages [24]. A persistent high level of proteinuria is associated with severe histological lesions, including high scores of Oxford classification parameters [4,23,25,26]. In our study proteinuria levels did not correlate with histological findings.…”

Section: Discussionmentioning

confidence: 49%

“…Other authors have reported a correlation with impaired renal function at the time of biopsy and long-term prognosis [23]. In patients with C4d negative biopsies a high number of interstitial macrophages correlated with impairment of renal function at the time of biopsy and at the end of follow-up, whereas the number of glomerular macrophages did not have any functional or prognostic value.…”

Section: Discussionmentioning

confidence: 76%

Prognostic value of morphologic and morphometric analyses in IgA nephropathy biopsies

et al. 2016

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Background: IgA nephropathy (IgAN) exhibits a variable course ranging from a benign condition to progressive renal failure with a high proportion of patients undergoing end-stage renal disease in the long term. It is unclear how to predict the risk of this progression. Mesangial C4d deposition has been found to be associated with a poor prognosis. Our aim was to search histological lesions with possible prognostic value in IgAN biopsies performed at the time of the diagnosis. Methods: Clinical and laboratory records of 44 patients undergoing renal biopsy were reviewed. IgAN was diagnosed in 32 patients and minimal change disease (MCD) in 12. C4d deposition, glomerular endothelial cell area, glomerular and interstitial macrophages were evaluated in all biopsies. Clinical and laboratory data were available in all IgAN patients at the time of diagnosis and in 21 patients at the end of follow-up (mean follow-up 48.09 ± 19.69 months). Results: All IgAN and MCD biopsies were C4d negative. The number of glomerular macrophages and the area of glomerular endothelial cells in IgAN were greater than in MCD (P < 0.001 and P < 0.0001, respectively), indicating glomerular inflammation associated with endothelial cell enlargement. Glomerular macrophages positively correlated with diffuse IgA and fibrinogen immunoreactivity (P < 0.02 and P < 0.002, respectively). Interstitial macrophages positively correlated with segmental glomerulosclerosis (P < 0.01) and tubular atrophy (P < 0.001), according to the Oxford classification. They correlated with hypertension (P < 0.03) and renal functional impairment both at the time of biopsy and at the end of follow-up. The receiver operating characteristic analysis curve and a cut-off value of ≥19.5 macrophages per high power field showed 75.0% sensitivity and 88.9% specificity in predicting worse clinical outcome. A Poisson generalized regression fit model showed that hypertension and tubular atrophy were the most significant factors in predicting a high number of interstitial macrophages. Conclusions: The number of interstitial macrophages correlated with hypertension, histological damage, functional impairment at the time of biopsy and worse outcome. A high number of interstitial macrophages in C4d negative biopsies may allow the identification of patients at increased risk of progression to renal failure.

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Renal macrophage infiltration is associated with a poor outcome in IgA nephropathy

Cited by 31 publications

References 28 publications

Osthole Mitigates Progressive IgA Nephropathy by Inhibiting Reactive Oxygen Species Generation and NF-κB/NLRP3 Pathway

Osthole Mitigates Progressive IgA Nephropathy by Inhibiting Reactive Oxygen Species Generation and NF-κB/NLRP3 Pathway

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

Prognostic value of morphologic and morphometric analyses in IgA nephropathy biopsies

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