MO447PROTEIN ARGININE METHYLTRANSFERASE 3 INHIBITS RENAL INTERSTITIAL FIBROSIS THROUGH ENHANCING RENAL ASYMMETRIC DIMETHYLARGININE LEVELS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Feng Yang ◽  
Ming Wu ◽  
Chaoyang Ye
Keyword(s):  
Renal Fibrosis ◽  
Asymmetric Dimethylarginine ◽  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Mutant Mice ◽  
Collagen I ◽  
Renal Interstitial Fibrosis ◽  
Arginine Methyltransferase ◽  
Masson Staining

Abstract Background and Aims Mammalian Protein Arginine Methyltransferase 3 (PRMT3) catalyzes the monomethylation and dimethylation of the Arginine residues of proteins. The role of PRMT3 in renal fibrosis is currently unknown. We aimed to study the role of PRMT3 in renal fibrosis and explored its underlining mechanisms. Method Sham or Unilateral Ureter Obstruction (UUO) operation was performed in Prmt3 wild-type (WT), heterozygous (Het) and homozygous (Homo) mutant mice, which were sacrificed at day 14. A single dose of aristolochic acid (5mg/kg) was injected in WT or HE mice, which was sacrificed at day 42. Results A strong interstitial fibrosis was observed in WT UUO mice as shown by Masson staining, and heterozygous or homozygous deletion of Prmt3 gene further enhanced interstitial fibrosis in mouse kidneys. The expression of collagen-I in mouse kidneys were analyzed by Western blotting. UUO operation increased the expression of collagen-I in WT mouse kidneys, which were further increased by genetic deletion of Prmt3 gene in a dose-dependent manner. A mild renal interstitial fibrosis was observed in AAN mice, which was enhanced by heterozygous deletion of Prmt3 gene. Western blot analysis showed that aristolochic acid increased the expression of collagen-I in WT mice, which was further increased in Prmt3 Het mutant mice. Mechanismly, asymmetric dimethylarginine levels were elevated in UUO or AAN mouse kidneys as compared with its controls as shown by immnohistochemistry staining or ELISA. Renal ADMA levels were not elevated in Prmt3 mutant UUO or AAN mice. Moreover, renal injection of ADMA in UUO kidneys blocked the enhanced renal interstitial fibrosis in Prmt3 Het mutant mice as shown by Masson staining and Western blot analysis of collagen-I. Conclusion Prmt3 inhibits renal interstitial fibrosis through enhancing renal ADMA levels.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

2008 ◽  
Vol 294 (2) ◽  
pp. H1058-H1066 ◽  
Author(s):  
Johannes Jacobi ◽  
Renke Maas ◽  
Nada Cordasic ◽  
Kilian Koch ◽  
Roland E. Schmieder ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Asymmetric Dimethylarginine ◽  
Interstitial Fibrosis ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Ang Ii ◽  
Renal Interstitial Fibrosis

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 μg·kg−1·min−1 ANG II, 3.0 μg·kg−1·min−1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

2021 ◽  
pp. 1-11
Author(s):  
Ting-Ting Liu ◽  
Ran Luo ◽  
Yi Yang ◽  
Yi-Chun Cheng ◽  
Dan Chang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Tube Formation ◽  
Renal Interstitial Fibrosis ◽  
Genetic Ablation ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries ◽  
Renal Tubular

<b><i>Introduction:</i></b> Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. <b><i>Methods:</i></b> We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. <b><i>Results:</i></b> We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. <b><i>Conclusion:</i></b> LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

scholarly journals Signaling Pathways Involved in Diabetic Renal Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuqing Zhang ◽  
De Jin ◽  
Xiaomin Kang ◽  
Rongrong Zhou ◽  
Yuting Sun ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
New Drugs ◽  
Therapeutic Effects ◽  
Renal Interstitial Fibrosis ◽  
Notch Pathways ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

scholarly journals Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3

2018 ◽  
Vol 315 (6) ◽  
pp. F1822-F1832 ◽  
Author(s):  
Zhengwei Ma ◽  
Qingqing Wei ◽  
Ming Zhang ◽  
Jian-Kang Chen ◽  
Zheng Dong
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Pathological Feature ◽  
Tubular Injury

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT- Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT- Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstitial fibrosis. Meanwhile, PT- Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT- Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2–3 mo old), significantly more Smad2/3 was induced in obstructed PT- Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

Pterostilbene, a Bioactive Component of Blueberries, Alleviates Renal Interstitial Fibrosis by Inhibiting Macrophage-Myofibroblast Transition

2020 ◽  
Vol 48 (07) ◽  
pp. 1715-1729
Author(s):  
Yanhuan Feng ◽  
Fan Guo ◽  
Hongxia Mai ◽  
Jing Liu ◽  
Zijing Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Fibrosis ◽  
Transcriptional Activity ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Rna Seq ◽  
Renal Interstitial Fibrosis ◽  
Bioactive Component

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the in vivo mouse unilateral ureteral obstruction (UUO) model and in vitro MMT cells. Kidneys subjected to UUO with PTB treatment were collected for the investigation of PTB mediating MMT derived renal interstitial fibrosis. We conducted kidney RNA-seq transcriptomes and TGF-[Formula: see text]1-induced bone marrow-derived macrophages assays to determine the mechanisms of PTB. We found that PTB treatment suppressed the interstitial fibrosis in UUO mice. PTB also attenuated the number of MMT cells in vivo and in vitro. The transcriptomic analysis showed that CXCL10 may play a central role in the process of PTB-treated renal fibrosis. The siRNA-mediated CXCL10 knockdown decreased the number of MMT cells in TGF-[Formula: see text]1-induced bone marrow-derived macrophages. Our results suggested that PTB attenuated renal interstitial fibrosis by mediating MMT by regulating transcriptional activity of CXCL10.

scholarly journals Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

2020 ◽  
Vol 31 (12) ◽  
pp. 2773-2792
Author(s):  
Markus Sellmayr ◽  
Moritz Roman Hernandez Petzsche ◽  
Qiuyue Ma ◽  
Nils Krüger ◽  
Helen Liapis ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Ckd Progression ◽  
Fticr Mass Spectrometry ◽  
Progressive Decline ◽  
Granulomatous Interstitial Nephritis ◽  
Crystal Nephropathy ◽  
Aristolochic Acid I

BackgroundThe roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.MethodsMALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.ResultsAsymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.ConclusionsAsymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.

Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice

2016 ◽  
Vol 130 (19) ◽  
pp. 1727-1739 ◽  
Author(s):  
Akiko Tanino ◽  
Takafumi Okura ◽  
Tomoaki Nagao ◽  
Masayoshi Kukida ◽  
Zuowei Pei ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Rat Kidney ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Renal Interstitial Fibrosis

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18−/− and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

scholarly journals miR-21 in ischemia/reperfusion injury: a double-edged sword?

2014 ◽  
Vol 46 (21) ◽  
pp. 789-797 ◽  
Author(s):  
Xialian Xu ◽  
Alison J. Kriegel ◽  
Xiaoyan Jiao ◽  
Hong Liu ◽  
Xiaowen Bai ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Renal Interstitial Fibrosis ◽  
Rna Molecules ◽  
Programmed Cell Death 4 ◽  
Proapoptotic Gene

MicroRNAs (miRNAs or miRs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the proapoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury; however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.

scholarly journals Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yao Xu ◽  
Yuqing Liu ◽  
Honglei Guo ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

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