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Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease.
Ishii K, Kobayashi H, Taguchi K, Guan N, Li A, Tong C, Davidoff O, Tran PV, Sharma M, Chandel NS, Kapp ME, Fogo AB, Brooks CR, Haase VH
(2020) Kidney Int :
Show Abstract · Added November 10, 2020
Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.
Copyright © 2020. Published by Elsevier Inc.
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1 Members
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0 MeSH Terms
Stabilization of Hypoxia-Inducible Factor Ameliorates Glomerular Injury Sensitization after Tubulointerstitial Injury.
Zou J, Yang J, Zhu X, Zhong J, Elshaer A, Matsusaka T, Pastan I, Haase VH, Yang HC, Fogo AB
(2020) Kidney Int :
Show Abstract · Added November 8, 2020
Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. At week six tubular injury markers normalized but with patchy collagen I and interstitial fibrosis. Pimonidazole staining, a hypoxia marker, was increased by folic acid treatment compared to vehicle while dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial hypoxia. The hematocrit was increased by dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury, inflammation and interstitial fibrosis were improved after dimethyloxalylglycine, with further reduced mortality, interstitial fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.
Copyright © 2020. Published by Elsevier Inc.
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1 Members
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0 MeSH Terms
Got glycogen? An energy resource in HIF-mediated prevention of ischemic kidney injury.
Haase VH
(2020) Kidney Int 97: 645-647
MeSH Terms: Glycogen, Kidney, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Up-Regulation
Show Abstract · Added March 24, 2020
Hypoxia-inducible factor activation reprograms glucose metabolism and leads to glycogen accumulation in multiple cell types. In this issue of Kidney International, Ito and colleagues demonstrate that pharmacologic inhibition of hypoxia-inducible factor-prolyl hydroxylase domain oxygen sensors in renal epithelial cells enhances glycogen synthesis and protects from subsequent hypoxia and glucose deprivation. In vivo studies advance the concept that renal glycogen metabolism contributes to cytoprotection afforded by pre-ischemic hypoxia-inducible factor-prolyl hydroxylase domain inhibition.
Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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1 Members
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5 MeSH Terms
Sirtuin 6 and renal injury: another link in the β-catenin chain?
Gewin LS
(2020) Kidney Int 97: 24-27
MeSH Terms: Fibrosis, Humans, Kidney, Kidney Diseases, Sirtuins, beta Catenin
Show Abstract · Added March 18, 2020
A protective role for sirtuin 6 (Sirt6) in the context of chronic renal injury is reported by Cai et al. in this issue of Kidney International. The mechanism is thought to be mediated by Sirt6's deacetylase activity, specifically on β-catenin target genes. This commentary discusses these results and the interaction between Sirt6 and β-catenin within the broader context of β-catenin signaling and injury.
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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1 Members
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6 MeSH Terms
Modeling human disease: a mouse model of acute kidney injury to chronic kidney disease progression after cardiac arrest.
Terker AS, de Caestecker M
(2020) Kidney Int 97: 22-24
MeSH Terms: Acute Kidney Injury, Animals, Cardio-Renal Syndrome, Disease Progression, Heart Arrest, Humans, Inflammation, Mice, Renal Insufficiency, Chronic
Show Abstract · Added May 10, 2020
Matsushita et al. describe a model of acute kidney injury to chronic kidney disease progression in mice surviving cardiac arrest: mice develop severe acute kidney injury that initially recovers but is followed by the onset of impaired renal function on longer-term follow-up. These findings suggest that distinct cardiorenal toxicities and/or injury dynamics are operative in this cardiac arrest model that do not occur in traditional models of acute kidney injury, providing new opportunities for therapeutic and biomarker discovery for an important clinical problem.
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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1 Members
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9 MeSH Terms
Peroxidasin Is a Novel Target of Autoantibodies in Lupus Nephritis.
Manral P, Colon S, Bhave G, Zhao MH, Jain S, Borza DB
(2019) Kidney Int Rep 4: 1004-1006
Added March 3, 2020
0 Communities
1 Members
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0 MeSH Terms
Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1.
Vanslambrouck JM, Woodard LE, Suhaimi N, Williams FM, Howden SE, Wilson SB, Lonsdale A, Er PX, Li J, Maksimovic J, Oshlack A, Wilson MH, Little MH
(2019) Kidney Int 95: 1153-1166
MeSH Terms: Cells, Cultured, Cellular Reprogramming, DNA Transposable Elements, Gene Transfer Techniques, Genetic Engineering, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Nephrons, Nuclear Proteins, Primary Cell Culture, Protein Tyrosine Phosphatases, Regeneration, Snail Family Transcription Factors
Show Abstract · Added March 28, 2019
All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost close to the time of birth. The generation of new nephron progenitors and their maintenance in culture are central to the success of kidney regenerative strategies. Using a lentiviral screening approach, we previously generated a human induced nephron progenitor-like state in vitro using a pool of six transcription factors. Here, we sought to develop a more efficient approach for direct reprogramming of human cells that could be applied in vivo. PiggyBac transposons are a non-viral integrating gene delivery system that is suitable for in vivo use and allows for simultaneous delivery of multiple genes. Using an inducible piggyBac transposon system, we optimized a protocol for the direct reprogramming of HK2 cells to induced nephron progenitor-like cells with expression of only 3 transcription factors (SNAI2, EYA1, and SIX1). Culture in conditions supportive of the nephron progenitor state further increased the expression of nephron progenitor genes. The refined protocol was then applied to primary human renal epithelial cells, which integrated into developing nephron structures in vitro and in vivo. Such inducible reprogramming to nephron progenitor-like cells could facilitate direct cellular reprogramming for kidney regeneration.
Copyright © 2019 International Society of Nephrology. All rights reserved.
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2 Members
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14 MeSH Terms
Action plan for determining and monitoring the prevalence of chronic kidney disease.
Coresh J, Hu JR, Bello AK, Feldman HI, Fogo AB, Ganji MR, Harris DC, Levey AS, Okpechi IG, Stengel B, Thomas B, Wiecek A, Gansevoort RT
(2017) Kidney Int Suppl (2011) 7: 63-70
Show Abstract · Added April 6, 2019
Chronic kidney disease (CKD) continues to remain high globally, up to 13.4% by one estimate. Although the number, geographic distribution, size, and quality of the studies examining CKD prevalence and incidence have increased over the past decade, the global capacity for CKD surveillance is still far less developed than that for hypertension, diabetes, and cardiovascular disease. Estimating CKD prevalence is constrained by inadequate standardization of serum creatinine and urine albumin assays, heterogeneity in study designs, lack of national registries in many countries, incomplete adoption of disease classification guidelines, and inconsistent use of evidence-based equations for estimating glomerular filtration rate. Goal 1: Improve monitoring of CKD prevalence. To achieve this, disseminate the rationale for CKD prevalence monitoring, achieve uniform measurement of CKD markers, promote inclusion of CKD measurements in all large chronic disease cohorts and health surveys, harness administrative claims data for CKD surveillance, and incorporate the new CKD classification system in the International Classification of Diseases. Goal 2: Improve CKD monitoring of populations underrepresented in studies to date. To achieve this, establish registries of chronic dialysis and transplantation in all countries; establish registries for special CKD groups, such as children, patients with rare diseases, and patients with special etiologies of CKD. Goal 3: Improve identification of individuals with CKD. To achieve this, implement the Kidney Disease: Improving Global Outcomes guidelines for screening and testing, carry out randomized studies on screening strategies, ensure that estimated glomerular filtration rate is reported with all reports of serum creatinine, and leverage new software for identification and follow-up of CKD cases.
0 Communities
1 Members
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0 MeSH Terms
Soluble ST2 and Galectin-3 and Progression of CKD.
Alam ML, Katz R, Bellovich KA, Bhat ZY, Brosius FC, de Boer IH, Gadegbeku CA, Gipson DS, Hawkins JJ, Himmelfarb J, Kestenbaum BR, Kretzler M, Robinson-Cohen C, Steigerwalt SP, Tuegel C, Bansal N
(2019) Kidney Int Rep 4: 103-111
Show Abstract · Added January 3, 2019
Introduction - Cardiac biomarkers soluble ST2 (sST2) and galectin-3 may reflect cardiac inflammation and fibrosis. It is plausible that these mechanisms may also contribute to the progression of kidney disease. We examined associations of sST2 and galectin-3 with kidney function decline in participants with chronic kidney disease (CKD).
Methods - This was a pooled analysis of 2 longitudinal cohorts of participants with CKD: the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS). We measured circulating concentrations of sST2 and galectin-3 at baseline. Our primary outcome was progression to estimated glomerular filtration rate (eGFR) <15 ml/min per 1.73 m or end-stage renal disease (ESRD). We used competing risk Cox regression models to study the association of sST2 and galectin-3 with CKD progression, adjusting for demographics, kidney function, and comorbidity.
Results - Among the 841 participants in the pooled cohort, baseline eGFR was 51 ± 27 ml/min per 1.73 m and median urine albumin-to-creatinine ratio (UACR) was 141 (interquartile range = 15-736) mg/g. Participants with higher sST2 and galectin-3 were more likely to be older, to have heart failure and diabetes, and to have lower eGFR. Adjusting for demographics, kidney function, and comorbidity, every doubling of sST2 was not associated with progression to eGFR <15 ml/min per 1.73 m or ESRD (adjusted hazard ratio 1.02, 95% confidence interval = 0.76-1.38). Every doubling of galectin-3 was significantly associated with a 38% (adjusted hazard ratio = 1.35, 95% confidence interval = 1.01-1.80) increased risk of progression to eGFR <15 ml/min per 1.73 m or ESRD.
Conclusion - Higher concentrations of the cardiac biomarker galectin-3 may be associated with progression of CKD, highlighting potential novel mechanisms that may contribute to the progression of kidney disease.
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1 Members
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0 MeSH Terms
Serum metabolites are associated with all-cause mortality in chronic kidney disease.
Hu JR, Coresh J, Inker LA, Levey AS, Zheng Z, Rebholz CM, Tin A, Appel LJ, Chen J, Sarnak MJ, Grams ME
(2018) Kidney Int 94: 381-389
MeSH Terms: Adult, Aged, Allantoin, Biomarkers, Cause of Death, Cohort Studies, Female, Follow-Up Studies, Fumarates, Humans, Kidney, Male, Metabolomics, Middle Aged, Renal Insufficiency, Chronic
Show Abstract · Added April 6, 2019
Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms