Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

Lehners, Alexander; Lange, Adam; Niemann, Gianina; Rosendahl, Alva; Meyer-Schwesinger, Catherine; Oh, Jun; Stahl, Rolf A.K.; Ehmke, Heimo; Benndorf, Ralf A.; Klinke, Anna; Baldus, Stephan; Wenzel, Ulrich

doi:10.1152/ajprenal.00262.2014

Cited by 40 publications

(41 citation statements)

References 42 publications

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“…In the present study, we observed evidence of inflammation seven days after Nx (data not shown), corroborating earlier findings 7, 22, 39 . However, we chose to start our analysis fifteen days after renal ablation, when activation of inflammatory mechanisms could no longer be attributed to residual effects of surgical manipulation.…”

Section: Discussionsupporting

confidence: 93%

“…Concomitant with these renal lesions, and even preceding them, the presence of inflammatory events such as infiltration by Mϕ and T-Ly was equally conspicuous. Previous studies reported even earlier activation of inflammatory mechanisms in the Nx model 1, 22, 39 , although the possibility that such response merely reflects the acute effect of surgical manipulation cannot be ruled out.…”

Section: Discussionmentioning

confidence: 87%

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Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

Fanelli

Arias

Machado

et al. 2017

Sci Rep

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The mechanisms triggering renal inflammation in chronic kidney disease (CKD) are unclear. We performed a detailed analysis of the time course of innate and adaptive immunity activation in the 5/6 renal ablation (Nx) model. Munich-Wistar rats undergoing Nx were studied 15, 60 and 120 days after ablation. Hypertension, albuminuria, creatinine retention, interstitial expansion and infiltration by macrophages and T-lymphocytes were already evident 15 days after Nx. PCR-array was used to screen for altered gene expression, whereas gene and protein expressions of TLR4, CASP1, IL-1β and NLRP3 were individually assessed. Tlr4, Tlr5, Lbp, Nlrp3, Casp1, Irf7 and Il1b were already upregulated 15 days after Nx, while activation of Tlr2, Tlr7, Tlr9, Nod2, Tnf and Il6 was seen after 60 days post-ablation. The number of genes related to innate or adaptive immunity grew steadily with time. These observations indicate that parallel activation of innate and adaptive immunity antecedes glomerular injury and involves a growing number of intricate signaling pathways, helping to explain the difficulty in detaining renal injury in Nx as CKD advances, and, stressing the need for early treatment. Additionally, these findings may contribute to the search of therapeutic targets specific for advanced phases of CKD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 87%

Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

Fanelli

Arias

Machado

et al. 2017

Sci Rep

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“…Systolic blood pressure was measured with a computerized tail-cuff system (Process Control Blood Pressure 2900 series, TSE Systems, Bad Homburg, Germany), as previously described (16,18,22). Mice were placed into metabolic cages for a 6-h urine collection.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse-specific PCR primers were used. Levels of mRNA expression in each sample were normalized to 18S rRNA expression (15,18). Flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

Weiß

Rosendahl

Czesla

et al. 2016

American Journal of Physiology-Renal Physiology

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Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.

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“…Basal MMP-2 and inducible MMP-9 primarily degrade collagen and laminin, major components of ECM (28). Although insufficient MMP-2 and MMP-9 may lead to ECM accumulation, the expression levels of MMP-2 and MMP-9 in DN remain controversial (29).…”

Section: Discussionmentioning

confidence: 99%

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Insufficient matrix metalloproteinase (MMP)-9 and MMP-2 is considered to be a contributor of extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can reverse fibrosis, thus exerting a beneficial effect on DN. Whether C-peptide induces MMP-9 and MMP-2 to reverse ECM accumulation is not clear. In the present study, in order to determine ECM metabolism, rat mesangial cells were treated with high glucose (HG) and C-peptide intervention, then the early and late effects of C-peptide on HG-affected MMP-9 and MMP-2 were evaluated. Firstly, it was confirmed that HG mainly suppressed MMP-9 expression levels. Furthermore, C-peptide treatment induced MMP-9 expression at 6 h and suppressed it at 24 h, revealing the early dual effects of C-peptide on MMP-9 expression. Subsequently, significant increase in MMP-9 expression at 72, 96 and 120 h C-peptide treatment was observed. These changes in MMP-9 protein content confirmed its expression changes following late C-peptide treatment. Furthermore, at 96 and 120 h C-peptide treatment reversed the HG-inhibited MMP-9 secretion, further indicating the late induction effect of C-peptide on MMP-9. The present results demonstrated that C-peptide exerted a late induction effect on MMP-9 in HG-stimulated rat mesangial cells, which may be associated with the underlying mechanism of C-peptide's reversal effects on DN. IntroductionDiabetic nephropathy (DN), the leading cause of end stage renal disease, is the major cause of mortality in type 1 diabetes mellitus (DM) and the second most severe complications in type 2 diabetes (1,2). Deposition of extracellular matrix (ECM) in mesangial areas is a feature of DN, and mesangial cells have been proposed to be the determinant of ECM accumulation (3,4). However, the mechanism underlying ECM accumulation in DN is not fully clarified.Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can degrade numerous types of ECM components (5,6). Among others, MMP-2 basally expresses while MMP-9 is an inducible enzyme, both of which primarily degrade types-I and -IV collagen and laminin, major components of ECM (7-9). Generally, MMP-2 and MMP-9 are involved in tumor metastasis (6,10). Furthermore, it has been shown that insufficient MMP-2 and MMP-9 may be a contributor of ECM accumulation in DN (11). However, the expression levels of MMP-2 and MMP-9 in DN remain controversial, and even short-and long-term hyperglycemia may exert differential effects (8,(12)(13)(14). As an inducible enzyme, MMP-9 may be more easily affected in patients with DN (15). Therefore, the changes of MMP-2, and particularly MMP-9, for high glucose (HG) stimulation require clarification.C-peptide is the linker between the A-chain and B-chain of insulin. Lack of C-peptide along with insulin is the primary feature of type 1 DM and late stage of type 2 DM (16). C-peptide has been found to have unique beneficial effects on DN, attenuating glomerular and tubular injury (17)(18)(19). Physiological concentration of C-peptide ca...

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Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

Cited by 40 publications

References 42 publications

Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

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