Loss of epigenetic information as a cause of mammalian aging

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 305 - 326.e27

Published: Jan. 1, 2023

Language: Английский

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Digital pathology and computational image analysis in nephropathology

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(11), P. 669 - 685

Published: Aug. 26, 2020

Language: Английский

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Glomerular Aging and Focal Global Glomerulosclerosis

Journal of the American Society of Nephrology, Journal Year: 2015, Volume and Issue: 26(12), P. 3162 - 3178

Published: June 3, 2015

Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured number, size, density, glomerular volume in 89 normal kidney samples from living deceased donors poles nephrectomies. Podocyte nuclear density decreased age due to combination number per glomerulus increased volume. Compensatory cell hypertrophy prevented change the tuft occupied podocytes. Young kidneys had high reserve (podocyte >300 106µm3), but 70–80 years age, average to, <100 106µm3, corresponding hypertrophy. older detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, kidneys, proteinaceous material accumulated Bowman space glomeruli low density. subset these mass events occurred association becoming binucleate (mitotic catastrophe) subsequent wrinkling capillaries, collapse, periglomerular fibrosis. young patients underlying diseases pathologic identified focal global glomerulosclerosis. reduction may therefore directly lead all progressive can considered superimposed accelerators this process.

Language: Английский

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Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease

Nature Reviews Nephrology, Journal Year: 2015, Volume and Issue: 11(9), P. 535 - 545

Published: June 9, 2015

Language: Английский

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Development and evaluation of deep learning–based segmentation of histologic structures in the kidney cortex with multiple histologic stains

Kidney International, Journal Year: 2020, Volume and Issue: 99(1), P. 86 - 101

Published: Aug. 21, 2020

The application of deep learning for automated segmentation (delineation boundaries) histologic primitives (structures) from whole slide images can facilitate the establishment novel protocols kidney biopsy assessment. Here, we developed and validated networks structures on biopsies nephrectomies. For development, examined 125 Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 stained Hematoxylin & Eosin (125), Periodic Acid Schiff Silver (102), Trichrome (107) divided into training, validation testing sets (ratio 6:1:3). Histologic were manually segmented (30048 total annotations) by five nephropathologists. Twenty models trained optimal digital magnification stains. Schiff-stained yielded best concordance between pathologists all (F-scores: 0.93 glomerular tufts, 0.94 tuft plus Bowman's capsule, 0.91 proximal tubules, distal tubular segments, 0.81 peritubular capillaries, 0.85 arteries afferent arterioles). Optimal magnifications 5X tuft/tuft 10X proximal/distal tubule, arterioles, 40X capillaries. worst performance. Thus, this largest study to date adapted multiple stains pathology laboratories. All data used training a detailed online tutorial will be publicly available.

Language: Английский

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Minimal change disease and idiopathic FSGS: manifestations of the same disease

Nature Reviews Nephrology, Journal Year: 2016, Volume and Issue: 12(12), P. 768 - 776

Published: Oct. 17, 2016

Language: Английский

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TLR4 Activation Promotes Podocyte Injury and Interstitial Fibrosis in Diabetic Nephropathy

PLoS ONE, Journal Year: 2014, Volume and Issue: 9(5), P. e97985 - e97985

Published: May 19, 2014

Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 complicated pathophysiology nephropathy is not understood. In this study, we report elevated expression TLR4, its endogenous ligands and downstream cytokines, chemokines fibrogenic genes WT mice with streptozotocin (STZ) diabetes. Subsequently, demonstrated that TLR4−/− were protected against development nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy hypercellularity, podocyte tubular injury as compared wild-type controls. Marked reductions interstitial collagen deposition, myofibroblast activation (α-SMA) (TGF-β fibronectin) also evident deficient mice. Consistent our vivo results, high glucose directly promoted podocytes epithelial cells vitro, resulting NF-κB consequent inflammatory responses. Our data indicate may cell fibrosis, suggesting a potential therapeutic target for

Language: Английский

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Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(50)

Published: Nov. 24, 2014

Significance Diabetic nephropathy is the leading cause of chronic kidney disease in United States, and one most significant long-term complications both type 1 2 diabetes, which currently lack fully effective therapy. Hyperglycemia activation renin-angiotensin system (RAS) are thought to be two main drivers this pathology. We have recently shown that selective blockade peripheral cannabinoid receptor-1 (CB R) delayed attenuated development diabetes a rat model. Here we show nephropathy-inducing effects hyperglycemia RAS involve CB R glomerular podocytes, antagonism could represent novel, effective, rational approach prevent reverse diabetic nephropathy.

Language: Английский

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MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes

Journal of Clinical Investigation, Journal Year: 2015, Volume and Issue: 125(11), P. 4091 - 4106

Published: Oct. 4, 2015

Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie regulation of calcium/calcineurin essential. Here, we showed components signaling, TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are targets microRNA-30 family (miR-30s). We found these 5 genes highly expressed as mRNA, but level proteins low podocytes. Conversely, protein levels were markedly elevated podocytes from rats treated with puromycin aminonucleoside (PAN) patients focal segmental glomerulosclerosis (FSGS). In both FSGS PAN-treated rats, miR-30s downregulated cultured podocytes, PAN or a miR-30 sponge increased NFATC3 expression; calcium influx; intracellular Ca2+ concentration; calcineurin activity. Moreover, nuclear translocation, synaptopodin degradation, integrin β3 (ITGB3) activation, actin fiber loss, which downstream induced by reduction blocked inhibitor FK506. Podocyte-specific expression mice component The developed podocyte foot process effacement proteinuria, prevented also regulated cardiomyocytes. Together, our results identify essential regulators signaling.

Language: Английский

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APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease

Journal of the American Society of Nephrology, Journal Year: 2016, Volume and Issue: 27(12), P. 3600 - 3610

Published: March 29, 2016

APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury unknown. Because is unique to humans and some primates, we created transgenic (Tg) mice using promoter nephrin-encoding Nphs1 express reference sequence (G0) or G2 variant podocytes, establishing Tg lines a spectrum expression levels. Podocytes from Tg-G0 Tg-G2 did not undergo necrosis, apoptosis, autophagic cell death vivo, even highly expressed transgenes. Further, develop pathology, proteinuria, azotemia as 300 days age. However, by 200 age, had significantly lower podocyte density than age-matched WT had, difference that was evident at weaning. Notably, pregnancy-associated phenotype encompassed eclampsia, preeclampsia, fetal/neonatal deaths, small litter sizes occurred more severely mice. Similar human placenta, placentas APOL1. Overall, these results suggest depletion could predispose individuals genotypes response second stressor, add other published evidence associating preeclampsia.

Language: Английский

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