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.

scholarly journals Traditional Chinese medicine: Pivotal role of the spleen in the metabolism of aristolochic acid I in rats is dependent on oatp2a1

2016 ◽  
Vol 14 (4) ◽  
pp. 3243-3250 ◽  
Author(s):  
Ting Xiang ◽  
Zhangbin Yang ◽  
Baoguo Sun ◽  
Haoxuan Luo ◽  
Shijun Zhang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Aristolochic Acid ◽  
Pivotal Role ◽  
Aristolochic Acid I

Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I

2011 ◽  
Vol 8 (6) ◽  
pp. 2183-2192 ◽  
Author(s):  
Xiang Xue ◽  
Li-Kun Gong ◽  
Kazuya Maeda ◽  
Yang Luan ◽  
Xin-Ming Qi ◽  
...  
Keyword(s):  
Aristolochic Acid ◽  
Organic Anion ◽  
Critical Role ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
Aristolochic Acid I

scholarly journals Determination of Aristolochic Acid in Botanicals and Dietary Supplements by Liquid Chromatography with Ultraviolet Detection and by Liquid Chromatography/Mass Spectrometry: Single Laboratory Validation Confirmation

2006 ◽  
Vol 89 (4) ◽  
pp. 942-959 ◽  
Author(s):  
William A Trujillo ◽  
Wendy R Sorenson ◽  
Paul La Luzerne ◽  
John W Austad ◽  
Darryl Sullivan
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Dietary Supplements ◽  
Aristolochic Acid ◽  
Automation System ◽  
Ultraviolet Detection ◽  
Relative Standard ◽  
Single Laboratory ◽  
Aristolochic Acid I

Abstract The presence of aristolochic acid in some dietary supplements is a concern to regulators and consumers. A method has been developed, by initially using a reference method as a guide, during single laboratory validation (SLV) for the determination of aristolochic acid I, also known as aristolochic acid A, in botanical species and dietary supplements at concentrations of approximately 2 to 32 μg/g. Higher levels were determined by dilution to fit the standard curve. Through the SLV, the method was optimized for quantification by liquid chromatography with ultraviolet detection (LC-UV) and LC/mass spectrometry (MS) confirmation. The test samples were extracted with organic solvent and water, then injected on a reverse phase LC column. Quantification was achieved with linear regression using a laboratory automation system. The SLV study included systematically optimizing the LC-UV method with regard to test sample size, fine grinding of solids, and solvent extraction efficiency. These parameters were varied in increments (and in separate optimization studies), in order to ensure that each parameter was individually studied; the test results include corresponding tables of parameter variations. In addition, the chromatographic conditions were optimized with respect to injection volume and detection wavelength. Precision studies produced overall relative standard deviation values from 2.44 up to 8.26% for aristolochic acid I. Mean recoveries were between 100 and 103% at the 2 μg/g level, between 102 and 103% at the 10 μg/g level, and 104% at the 30 μg/g level.

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.

scholarly journals Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

2020 ◽  
Vol 21 (8) ◽  
pp. 2806 ◽  
Author(s):  
Priscila Calle ◽  
Georgina Hotter
Keyword(s):  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Vascular Dysfunction ◽  
Inflammatory Cells ◽  
Macrophage Phenotype ◽  
Progressive Decline ◽  
Potential Factors ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.

scholarly journals Selective Wnt/β-Catenin Pathway Activation Concomitant With Sustained Overexpression of miR-21 is Responsible for Aristolochic Acid-Induced AKI-to-CKD Transition

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Kuang ◽  
Sheng Wu ◽  
Ning Xue ◽  
Xiaoyan Wang ◽  
Xiaoqianq Ding ◽  
...  
Keyword(s):  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Cumulative Risk ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Ckd Progression ◽  
Renal Interstitial Fibrosis ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Acute kidney injury (AKI) is increasingly recognized as a cumulative risk factor for chronic kidney disease (CKD) progression. However, the underlying mechanisms remain unclear. Using an aristolochic acid (AA)-induced mouse model of AKI-to-CKD transition, we found that the development of tubulointerstitial fibrosis following AKI was accompanied with a strong activation of miR-21 and canonical Wnt signaling, whereas inhibition of miR-21 or selective silencing of Wnt ligands partially attenuated AKI-to-CKD transition. To explore the interaction between miR-21 and Wnt/β-catenin signaling, we examined the effects of genetic absence or pharmacologic inhibition of miR-21 on Wnt/β-catenin pathway expression. In miR-21−/− mice and in wild-type mice treated with anti-miR21 oligos, Wnt1 and Wnt4 canonical signaling in the renal tissue was significantly reduced, with partial reversal of renal interstitial fibrosis. Although the renal abundance of miR-21 remained unchanged after inhibition or activation of Wnt/β-catenin signaling, early intervention with ICG-001, a β-catenin inhibitor, significantly attenuated renal interstitial fibrosis. Moreover, early (within 24 h), but not late β-catenin inhibition after AA administration attenuated AA-induced apoptosis and inflammation. In conclusion, inhibition of miR-21 or β-catenin signaling may be an effective approach to prevent AKI-to-CKD progression.

scholarly journals Renoprotective effect of Stat1 deletion in murine aristolochic acid nephropathy

2020 ◽  
Author(s):  
Wenguang Feng ◽  
Wei-Zhong Ying ◽  
Xingsheng Li ◽  
Lisa M. Curtis ◽  
Paul W. Sanders
Keyword(s):  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Loss Of Function ◽  
Wild Type ◽  
Control Groups ◽  
Injury Score ◽  
Creatinine Concentration

Injured tubule epithelium stimulates a pro-fibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of STAT1 in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild type (WT) littermates treated with AA, while Stat1-/- mice were protected. Focal increases in the apical expression of Kidney Injury Molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment, but was absent in Stat1-/- mice in the treatment group as well as in both control groups. A Composite Injury Score, an indicator of proximal tubule injury, was reduced in Stat1-/- mice treated with AA. Expression of integrin β6 and p-Smad2/3 in proximal tubules and interstitial collagen and fibronectin were observed in WT mice following AA treatment, but were all decreased in AA-treated Stat1-/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.

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