scholarly journals APOL1-G0protects podocytes in a mouse model of HIV-associated nephropathy

2019 ◽  
Author(s):  
Leslie A. Bruggeman ◽  
Zhenzhen Wu ◽  
Liping Luo ◽  
Sethu Madhavan ◽  
Paul E. Drawz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Kidney Diseases ◽  
Cell Damage ◽  
Loss Of Function ◽  
Protective Function ◽  
Chronic Kidney Diseases ◽  
Increased Risk ◽  
Podocyte Loss ◽  
And Function

ABSTRACTBackgroundAfrican polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood.MethodsThe podocyte function ofAPOL1-G0versusAPOL1-G2in the setting of a known disease stressor was assessed using transgenic mouse models. Survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express eitherAPOL1-G0orAPOL1-G2in podocytes.ResultsMice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressedAPOL1-G0and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressingAPOL1-G2and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV andAPOL1-G0, but absent in the mice co-expressing HIV andAPOL1-G2. Mortality and renal function tests were not significantly different between groups.ConclusionsAPOL1-G0expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This function appears to be absent withAPOL1-G2expression, suggestingAPOL1-G2is a loss-of-function variant.

The Role of the CX3CL1-CX3CR1 Axis in Renal Disease

2021 ◽  
Author(s):  
Diana Hamdan ◽  
Lisa A. Robinson
Keyword(s):  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Transmembrane Protein ◽  
Soluble Form ◽  
Protective Effects ◽  
Chronic Kidney Diseases ◽  
The Family ◽  
Soluble Species ◽  
And Function

Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines are key drivers of this process. CX3CL1 (fractalkine) is one of two unique chemokines synthesized as a transmembrane protein which undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, CX3CR1, CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form, and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.

scholarly journals Lysophosphatidic Acid Signaling in Diabetic Nephropathy

2019 ◽  
Vol 20 (11) ◽  
pp. 2850 ◽  
Author(s):  
Jong Lee ◽  
Donghee Kim ◽  
Yoon Oh ◽  
Hee-Sook Jun
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathways ◽  
Lysophosphatidic Acid ◽  
Kidney Diseases ◽  
Cell Damage ◽  
Cell Structure ◽  
Research Findings ◽  
Stage Renal Disease ◽  
End Stage ◽  
And Function

Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such as cell proliferation, migration, and apoptosis. LPA also induces cell damage through complex overlapping pathways, including the generation of reactive oxygen species, inflammatory cytokines, and fibrosis. Several reports indicate that the LPA–LPAR axis plays an important role in various diseases, including kidney disease, lung fibrosis, and cancer. Diabetic nephropathy (DN) is one of the most common diabetic complications and the main risk factor for chronic kidney diseases, which mostly progress to end-stage renal disease. There is also growing evidence indicating that the LPA–LPAR axis also plays an important role in inducing pathological alterations of cell structure and function in the kidneys. In this review, we will discuss key mediators or signaling pathways activated by LPA and summarize recent research findings associated with DN.

scholarly journals The Cumulative Exposure to High-Sensitivity C-Reactive Protein Predicts the Risk of Chronic Kidney Diseases

2019 ◽  
Vol 45 (1) ◽  
pp. 84-94
Author(s):  
Jingli Gao ◽  
Aitian Wang ◽  
Xiaolan Li ◽  
Junjuan Li ◽  
Hualing Zhao ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
High Sensitivity ◽  
Cox Proportional Hazards ◽  
Exposed Group ◽  
Cumulative Exposure ◽  
C Reactive Protein ◽  
Chronic Kidney Diseases ◽  
Reactive Protein ◽  
Increased Risk ◽  
Hs Crp

Background and Objectives: This study was to characterize the association of cumulative exposure to increased high-sensitivity C-reactive protein (hs-CRP) with chronic kidney diseases (CKD). Methods: We included 35,194 participants with hs-CRP measured at three examinations in 2006, 2008, 2010. Participants were classified into nonexposed group (hs-CRP <3.0 mg/L in all 3 examinations), 1-exposed group (hs-CRP ≥3.0 mg/L in 1 of the 3 examinations), 2-exposed group (hs-CRP ≥3.0 mg/L in 2 of the 3 examinations), and 3-exposed group (hs-CRP ≥3.0 mg/L in 3 examinations). Cox proportional hazards models were used to assess the association of cumulative hs-CRP with incident CKD. CKD includes an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or urinary protein positive. Results: The study showed the risk of CKD as the number of years of exposure to hs-CRP increases. Participants in 3-exposed group had significantly increased CKD risk with hazard ratio (HR) (95% confidence interval, CI) of 1.70 (1.49–1.93), in comparison with 1.47 (1.34–1.62) for participants in the 2-exposed group, and 1.08 (1.00–1.16) for those in the 1-exposed group (p < 0.01); meanwhile, the similar and significant associations were also observed for eGFR <60 mL/min/1.73 m2, proteinuria positive, in participants of the 3-exposed group in comparison with the nonexposed group, with respective HRs (95% CI) of 1.27 (1.01–1.58) and 2.27 (1.87–2.76). Conclusions: Cumulative exposure to hs-CRP was associated with a subsequent increased risk of CKD and was of great value to risk prediction.

Combination of FXI Antisense Oligonucleotide and Plavix® Treatment Results in Enhanced Antithrombotic Activity without Increased Risk of Bleeding in Mouse Models of Thrombosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4173-4173
Author(s):  
Dacao Gao ◽  
Jeff Crosby ◽  
Robert MacLeod ◽  
Gourab Bhattacharjee ◽  
Ester C Lowenberg ◽  
...  
Keyword(s):  
Mouse Models ◽  
Antisense Oligonucleotide ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Fibrin Clot ◽  
Bleeding Tendency ◽  
Loss Of Function ◽  
Factor Xi ◽  
Antithrombotic Activity ◽  
Increased Risk

Abstract Abstract 4173 Factor XI (FXI) is a serine protease produced in the liver that contributes to thrombin generation via the intrinsic coagulation pathway. Also, it is a key component of an amplification pathway that is thought to sustain thrombin production at a wound site to maintain fibrin clot integrity. Loss of function mutations in the human FXI gene results in FXI deficiency, a disorder which is associated with only mild bleeding. In addition, high levels of FXI are a risk factor for thrombosis. We have previously presented the antithrombotic efficacy and safety of antisense oligonucleotide (ASO) mediated FXI depletion in various animal models of thrombosis. We have demonstrated that in combination with Lovenox®, FXI ASO treatment increases antithrombotic activity but does not increase bleeding risk. The purpose of the current study was to evaluate the relative risk/benefit of ASO mediated Factor XI depletion in combination with the platelet antagonist Plavix®. The “risk” component was bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was antithrombotic effect in arterial and venous mouse models of thrombosis. Our study investigated a 20 mg/kg dose of FXI ASO in combination with a dose response of Plavix® and indicates that antisense mediated FXI depletion provides enhanced antithrombotic protection when given in combination with Plavix®. The combination of FXI ASO and Plavix® did not result in increased bleeding tendency. In contrast, treatment with a small molecule inhibitor of factor Xa in combination with Plavix® significantly increased bleeding. The approach used in this study is being used to define the ability of FXI ASO to combine with standard of care agents for the treatment of thrombosis. Disclosures: Gao: Isis Pharmaceuticals, Inc.: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. MacLeod:Isis Pharmaceuticals: Employment. Bhattacharjee:Isis Pharmaceuticals, Inc.: Employment. Lowenberg:Isis Pharmaceuticals, Inc.: Consultancy. Levi:Isis Pharmaceuticals, Inc.: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment.

scholarly journals High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production

2011 ◽  
Vol 300 (6) ◽  
pp. E1047-E1058 ◽  
Author(s):  
Christine Ruggiero ◽  
Marilyn Ehrenshaft ◽  
Ellen Cleland ◽  
Krisztian Stadler
Keyword(s):  
Oxidative Stress ◽  
High Fat Diet ◽  
Respiratory Function ◽  
Kidney Diseases ◽  
Redox Status ◽  
Ros Generation ◽  
High Fat ◽  
Chronic Kidney Diseases ◽  
Mitochondrial Ros ◽  
Increased Risk

Obesity and metabolic syndrome are associated with an increased risk for several diabetic complications, including diabetic nephropathy and chronic kidney diseases. Oxidative stress and mitochondrial dysfunction are often proposed mechanisms in various organs in obesity models, but limited data are available on the kidney. Here, we fed a lard-based high-fat diet to mice to investigate structural changes, cellular and subcellular oxidative stress and redox status, and mitochondrial biogenesis and function in the kidney. The diet induced characteristic changes, including glomerular hypertrophy, fibrosis, and interstitial scarring, which were accompanied by a proinflammatory transition. We demonstrate evidence for oxidative stress in the kidney through 3-nitrotyrosine and protein radical formation on high-fat diet with a contribution from iNOS and NOX-4 as well as increased generation of mitochondrial oxidants on carbohydrate- and lipid-based substrates. The increased H2O2 emission in the mitochondria suggests altered redox balance and mitochondrial ROS generation, contributing to the overall oxidative stress. No major derailments were observed in respiratory function or biogenesis, indicating preserved and initially improved bioenergetic parameters and energy production. We suggest that, regardless of the oxidative stress events, the kidney developed an adaptation to maintain normal respiratory function as a possible response to an increased lipid overload. These findings provide new insights into the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of the kidney in obesity and indicate that early oxidative stress-related changes, but not mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development of obesity-linked chronic kidney diseases.

scholarly journals Aquaporins in Renal Diseases

2019 ◽  
Vol 20 (2) ◽  
pp. 366 ◽  
Author(s):  
Jinzhao He ◽  
Baoxue Yang
Keyword(s):  
Kidney Diseases ◽  
Kidney Injury ◽  
Concentration Function ◽  
Urine Concentration ◽  
Renal Diseases ◽  
Chronic Kidney Diseases ◽  
Transmembrane Channels ◽  
Normal Urine ◽  
And Function ◽  
Urine Concentrating Ability

Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. Eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells in the kidney to maintain normal urine concentration function. AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation. Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus. Studies with animal models show AQPs are related to acute kidney injury and various chronic kidney diseases, such as diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma. Experimental data suggest ideal prospects for AQPs as biomarkers and therapeutic targets in clinic. This review article mainly focuses on recent advances in studying AQPs in renal diseases.

scholarly journals Macrophage Phenotype in Kidney Injury and Repair

2015 ◽  
Vol 1 (2) ◽  
pp. 138-146 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Patrick Ming-Kuen Tang ◽  
Jun Li ◽  
Hui Yao Lan
Keyword(s):  
Renal Injury ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Chronic Kidney Diseases ◽  
Chronic Kidney Injury ◽  
Injury And Repair ◽  
And Function

Background: Glomerular and interstitial macrophage infiltration is a feature for both the acute and chronic kidney diseases. Macrophages have been shown to play a diverse role in kidney injury and repair. Thus, macrophages may be a key cell type in acute and chronic kidney injury and repair. Summary and Key Messages: During renal inflammation, circulating monocytes are recruited and then become activated and polarized. By adapting to the local microenvironment, macrophages can differentiate into different phenotypes and function as a double-bladed sword in different stages of kidney disease. In general, M1 macrophages play a pathogenic role in boosting inflammatory renal injury, whereas M2 macrophages exert an anti-inflammatory and wound healing (or profibrotic) role during renal repair. In this review, we highlight the phenotypic polarization of macrophages in renal diseases and dissect their distinct functions in renal injury and repair processes, respectively. Moreover, the current understanding of regulatory mechanisms on the phenotypic switch and macrophage-related therapy are also intensively discussed.

scholarly journals Transcript profiles of stria vascularis in models of Waardenburg syndrome

2019 ◽  
Author(s):  
Linjun Chen ◽  
Yi Wang ◽  
Lei Chen ◽  
Fangyuan wang ◽  
Fei Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Mouse Models ◽  
Stria Vascularis ◽  
Specific Gene ◽  
Waardenburg Syndrome ◽  
Significant Difference ◽  
Tyrosine Metabolism ◽  
Transcript Profiles ◽  
And Function

Abstract Background: Waardenburg syndrome is a common syndromic hereditary deafness disease caused by stria vascularis dysfunction. However, the genetic pathway affecting stria vascularis development is still not clear. In this paper, the transcript profile of stria vascularis of Waardenburg syndrome was studied using Mitf-M mutant pigs and mice models. GO analysis was performed to identify the differential gene expression caused by Mitf-M mutation. Results: There were over than one hundred genes mainly found in tyrosine metabolism, melanin formation and ion transportations showed significant changes in both models. In addition, there were some spiced specific gene changes in the stria vascularis in the mouse and porcine models. The expression of tight junction-associated genes, including Cadm1, Cldn11, Pcdh1, Pcdh19 and Cdh24 genes , were significantly higher in porcine models compared to mouse models. Vascular-related and ion channel-related genes in the stria vascularis were also shown significantly difference between the two species. The expression of Col2a1, Col3a1, Col11a1 and Col11a2 genes were higher and the expression of Col8a2, Cd34 and Ncam genes were lower in the porcine model compared to mouse model. In both models, Trpm1, Kcnj13, and Slc45a2 genes were both affected by the Mitf-M mutation. In the pig models, the expression of Kcnn1, Clcn2 and Trpm4 genes were higher than the mouse model; whereas the expression of Trpm7, Kcnq1 and Kcnj8 genes were higher in the mouse models than the pig models. However, there was no significant difference in the morphology of the stria vascularis between these two models. Conclusions: Our data suggests that there is a significant difference on the gene expression and function between these two models.

Mouse Models of Muscular Dystrophy: Gene Products and Function

Physiology ◽  
1992 ◽  
Vol 7 (5) ◽  
pp. 195-199
Author(s):  
J Dangain ◽  
IR Neering
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Gene Product ◽  
Mouse Models ◽  
Autosomal Gene ◽  
Mdx Mouse ◽  
Gene Products ◽  
Linked Gene ◽  
Mouse Mutants ◽  
And Function

With the discovery of the X-linked gene product dystrophin, the mdx mouse came to be regarded as the only suitable mouse model of human muscular dystrophy. However, existence of an autosomal gene homologous with dystrophin, together with physiological evidence of membrane fragility, reestablishes autosomal mouse mutants (dy, dy2j) as valid models.

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