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Mashup Score: 26cGAS Activation Accelerates the Progression of Autosomal... : Journal of the American Society of Nephrology - 2 day(s) ago
mechanistic link between the deficiency polycystin-1 and mitochondrial homeostasis and the activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of the interferon genes (STING) pathway. Our data identify cGAS as an important mediator of renal cystogenesis and suggest that its inhibition may be useful to slow down the disease progression. Background Immune cells significantly contribute to the progression of autosomal dominant polycystic kidney disease (ADPKD), the most common genetic disorder of the kidney caused by the dysregulation of the Pkd1 or Pkd2 genes. However, the mechanisms triggering the immune cells recruitment and activation are undefined. Methods Immortalized murine collecting duct cell lines were used to dissect the molecular mechanism of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activation in the context of genotoxic stress induced by Pkd1 ablation. We used conditional Pkd1 and knockout cGas−/− g
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Mashup Score: 11Grainyhead-like 2 Deficiency and Kidney Cyst Growth in a... : Journal of the American Society of Nephrology - 3 day(s) ago
affected by Autosomal Dominant Polycystic Kidney Disease (ADPKD). However, the specific role of GRHL2 in cystic kidney disease remains unknown. Methods The functional role of the transcription factor Grhl2 in the context of cystic kidney disease was examined through analysis of its expression pattern in patient samples with ADPKD and generating a transgenic cystic kidney disease (TCKD) mouse model by overexpressing the human proto-oncogene c-MYC in kidney collecting ducts. Next, TCKD mice bred with collecting duct-specific Grhl2 knockout mice (Grhl2KO). The resulting TCKD-Grhl2KO mice and their littermates were examined by various types of histological and biochemical assays and gene profiling analysis via RNA-seq. Results A comprehensive examination of kidney samples from patients with ADPKD revealed GRHL2 downregulation in collecting duct-derived cyst epithelia. Comparative analysis of TCKD and TCKD-Grhl2KO mice exhibited that the collecting duct-specific deletion of Grhl2 resulted i
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The transcription factor Grainyhead-like 2 (GRHL2) plays a crucial role in maintaining epithelial barrier properties of the renal collecting duct. This study suggests GRHL2 is a progression modifier, especially for cysts originating from collecting ducts https://t.co/U0d5esqAJ8 https://t.co/pXPuuVilmk
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Mashup Score: 14American Society of Nephrology Kidney TREKS Program : Journal of the American Society of Nephrology - 3 day(s) ago
ows. The program combines a one-week intensive exposure to kidney physiology with a longitudinal mentorship program at the participants’ home institutions. Ten years in, an analysis was conducted to assess its effectiveness. We surveyed participants to assess their opinions regarding nephrology before and after the course and followed them longitudinally to determine their career choices. TREKS applicants who were not selected to participate were used as a comparison group. 381 people participated in the program and 242 completed the survey. After TREKS, both medical students and graduate students showed increased interest in nephrology, with rank scores of 5.6±0.2 pre- to 7.5±0.1 post-course for medical students (mean ± standard deviation, n=189, p=0.001) and 7.3±0.3 to 8.7±0.3 (n=53, p=0.001) for graduate students. In long term follow-up, TREKS medical students chose a nephrology pipeline residency at a higher rate than medical students overall (57% vs. 31%, p=0.01) and TREKS applica
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Mashup Score: 41Acute Kidney Injury Receiving Dialysis and Dialysis Care... : Journal of the American Society of Nephrology - 4 day(s) ago
scontinue dialysis. Data to inform dialysis management strategies that promote kidney function recovery and processes of care among individuals with AKI-D receiving outpatient dialysis are lacking. In this article, we detail current trends in the incidence, risk factors, clinical outcomes, proposed management, and health policy landscape for individuals with AKI-D receiving outpatient dialysis and identify areas for further research. The number of individuals with acute kidney injury receiving outpatient dialysis (AKI-D) is increasing. At present, based on limited data, approximately one third of individuals with AKI-D who receive outpatient dialysis after hospital discharge survive and regain sufficient kidney function to discontinue dialysis. Data to inform dialysis management strategies that promote kidney function recovery and processes of care among individuals with AKI-D receiving outpatient dialysis are lacking. In this article, we detail current trends in the incidence, risk fa
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Mashup Score: 28Plasma Proteins associated with Chronic Histopathologic... : Journal of the American Society of Nephrology - 4 day(s) ago
otential to enhance CKD care. Methods: We examined the association between 6592 plasma protein levels measured by aptamers and the severity of interstitial fibrosis and tubular atrophy (IFTA), glomerulosclerosis, arteriolar sclerosis, and arterial sclerosis among 434 participants of the Boston Kidney Biopsy Cohort. For proteins significantly associated with at least one histologic lesion, we assessed renal arteriovenous protein gradients among 21 individuals who had undergone invasive catheterization and assessed the expression of the cognate gene among 47 individuals with single cell RNA sequencing data in the Kidney Precision Medicine Project. Results: In models adjusted for estimated glomerular filtration rate (eGFR), proteinuria, and demographic factors, we identified 35 proteins associated with one or more chronic histologic lesions, including 20 specific for IFTA, 8 specific for glomerulosclerosis, and 1 specific for arteriolar sclerosis. In general, higher levels of these protei
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Mashup Score: 38Spatiotemporal Landscape of Kidney Tubular Responses to... : Journal of the American Society of Nephrology - 5 day(s) ago
understand the cellular changes that mediate these important clinical phenomena. Methods We conducted single nuclei RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these were altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days. Results Glomerular proteinuria activated large-scale and pleotropic changes in gene expression in all major nephron sections. Extension of protein uptake from early (S1) to later (S2) parts of the proximal tubule initially triggered dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of loss of canonical S2 functions. Proteinuria also induced acute injury in S3. Meanwhile, overflow of luminal proteins to the distal tubule caused transcriptional convergence between specialized regions and generalized dedifferentiation. Conclusions Proteinuria mo
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Mashup Score: 11The Ip6k1 and Ip6k2 Kinases Are Critical for Normal Renal... : Journal of the American Society of Nephrology - 5 day(s) ago
tasis is mostly unknown. We demonstrate in a renal cell line and in mice that Ip6k1 and Ip6k2 are critical for normal expression and function of the major renal Na+/Pi transporters NaPi-IIa and NaPi-IIc. Moreover, Ip6k1/2−/− mice also show symptoms of more generalized kidney dysfunction. Thus, our results suggest that IP6Ks are essential for phosphate metabolism and proper kidney function in mammals. Background Inorganic phosphate is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining phosphate homeostasis through mechanisms that ultimately regulate the expression of the Na+/Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP7, generated by IP6Ks, is a main regulator of phosphate metabolism in yeast and plants. IP6Ks are conserved in mammals, but their role in phosphate metabolism in vivo remains unexplored. Methods We used in vitro (opossum kidney cells) and in vivo (renal tubular-spec
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Mashup Score: 10Enriched Single-Nucleus RNA-Sequencing Reveals Unique... : Journal of the American Society of Nephrology - 6 day(s) ago
abundant magnesium-handling genes along DCT1 and more calcium-handling genes along DCT2. The data also provide insight into the plasticity of the distal nephron-collecting duct junction, formed from cells of separate embryonic origins. By focusing/changing gradients of gene expression, the DCT can morph into different physiological cell states on demand. Background The distal convoluted tubule (DCT) comprises two subsegments, DCT1 and DCT2, with different functional and molecular characteristics. The functional and molecular distinction between these segments, however, has been controversial. Methods To understand the heterogeneity within the DCT population with better clarity, we enriched for DCT nuclei by using a mouse line combining “Isolation of Nuclei Tagged in specific Cell Types” and sodium chloride cotransporter–driven inducible Cre recombinase. We sorted the fluorescently labeled DCT nuclei using Fluorescence-Activated Nucleus Sorting and performed single-nucleus transcriptomi
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Mashup Score: 14Integrated Proteomic and Metabolomic Modules associated... : Journal of the American Society of Nephrology - 6 day(s) ago
udy (N=1,708; average follow-up for kidney failure [KF], 9.5 years, with 537 events). Proteins and metabolites were integrated using an unsupervised clustering method and we assessed associations between clusters and CKD progression and kidney failure using Cox proportional hazards models. Analyses were adjusted for demographics and risk factors including the estimated glomerular filtration rate (eGFR) and urine protein–creatinine ratio. Associations were identified in a discovery sample (random two-thirds, N=1139) and then evaluated in a replication sample (one-third, N=569). Results: We identified 139 modules of correlated proteins and metabolites, which were represented by their principal components (PC). Modules and PC loadings were projected onto the replication sample which demonstrated a consistent network structure. Two modules, representing a total of 236 proteins and 82 metabolites, were robustly associated with both CKD progression and kidney failure in both discovery and va
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Mashup Score: 50The Clinical Relevance of the Infiltrating Immune Cell... : Journal of the American Society of Nephrology - 9 day(s) ago
er large scale studies of the relationship between cell infiltrate profiles and histological heterogeneity. Methods: In this cross-sectional study, we assessed the composition of nine intragraft immune cell types by using a validated kidney transplant-specific signature matrix for deconvolution of bulk transcriptomics in three different kidney transplant biopsy datasets (N=403, N=224, N=282). The association and the discrimination of the immune cell types with the Banff histology and the association with graft failure were assessed individually and with multivariable models. Unsupervised clustering algorithms were applied on the overall immune cells composition and compared to the Banff phenotypes. Results: Banff-defined rejection was related to high presence of CD8+ effector T cells, Natural Killer cells, monocytes/macrophages and to a lesser extent B cells, whereas CD4+ memory T cells were lower in rejection compared to no rejection. Estimated intragraft effector memory–expressing CD
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The link between the histology of kidney transplant rejection and the types of infiltrating immune cells is not well charted. This study found the estimated immune cell composition of kidney transplants is ill related to Banff-defined rejection categories https://t.co/lzOnRZxobH https://t.co/gYAYTf946p
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Immune cells significantly contribute to the progression of ADPKD. This study indicates that the activation of the cGAS/STING pathway contributes to ADPKD cystogenesis through the control of the immune response associated with the loss of Pkd1 https://t.co/n3NfkQDawD @azeloglu https://t.co/Ct3vIhpaXu