| 1. |
- Butt, Linus, et al.
(författare)
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A molecular mechanism explaining albuminuria in kidney disease
- 2020
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 2:5, s. 461-474
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian kidneys constantly filter large amounts of liquid, with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney disease. However, exactly how the renal filter works and why its permeability is altered in kidney diseases is poorly understood. Here we show that the permeability of the renal filter is modulated through compression of the capillary wall. We collect morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease affecting the renal filtration barrier. Combining quantitative analyses with mathematical modelling, we demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. Our results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.
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| 2. |
- Butt, Linus, et al.
(författare)
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Super-Resolution Imaging of the Filtration Barrier Suggests a Role for Podocin R229Q in Genetic Predisposition to Glomerular Disease
- 2021
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Ingår i: Journal of the American Society of Nephrology. - : Wolters Kluwer. - 1046-6673 .- 1533-3450. ; 33:1, s. 138-154
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Tidskriftsartikel (refereegranskat)abstract
- Significance Statement Podocin R229Q results from the most frequent missense variant in NPHS2, and its association with FSGS when podocin R229Q is transassociated with a second mutation in NPHS2 is well recognized. However, because results from observational studies are ambiguous and appropriate animal studies are lacking, its isolated pathogenic potency is not entirely clear. In this study, the authors introduced this genetic alteration in mice and assessed the phenotype using super-resolution microscopy and albuminuria measurements. They demonstrated a deleterious effect of the variant on podocyte morphology and on the integrity of the glomerular filtration barrier under basal conditions and after external glomerular injury. Because this finding suggests that this mutation confers a genetic predisposition to glomerular disease, it has implications for a large number of carriers worldwide.Background Diseases of the kidney’s glomerular filtration barrier are a leading cause of end stage renal failure. Despite a growing understanding of genes involved in glomerular disorders in children, the vast majority of adult patients lack a clear genetic diagnosis. The protein podocin p.R229Q, which results from the most common missense variant in NPHS2, is enriched in cohorts of patients with FSGS. However, p.R229Q has been proposed to cause disease only when transassociated with specific additional genetic alterations, and population-based epidemiologic studies on its association with albuminuria yielded ambiguous results.Methods To test whether podocin p.R229Q may also predispose to the complex disease pathogenesis in adults, we introduced the exact genetic alteration in mice using CRISPR/Cas9-based genome editing (PodR231Q). We assessed the phenotype using super-resolution microscopy and albuminuria measurements and evaluated the stability of the mutant protein in cell culture experiments.Results Heterozygous PodR231Q/wild-type mice did not present any overt kidney disease or proteinuria. However, homozygous PodR231Q/R231Q mice developed increased levels of albuminuria with age, and super-resolution microscopy revealed preceding ultrastructural morphologic alterations that were recently linked to disease predisposition. When injected with nephrotoxic serum to induce glomerular injury, heterozygous PodR231Q/wild-type mice showed a more severe course of disease compared with Podwild-type/wild-type mice. Podocin protein levels were decreased in PodR231Q/wild-type and PodR231Q/R231Q mice as well as in human cultured podocytes expressing the podocinR231Q variant. Our in vitro experiments indicate an underlying increased proteasomal degradation.Conclusions Our findings demonstrate that podocin R231Q exerts a pathogenic effect on its own, supporting the concept of podocin R229Q contributing to genetic predisposition in adult patients.
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| 3. |
- Reilly, T., et al.
(författare)
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Occupational fitness standards for beach lifeguards. Phase 2 : the development of an easily administered fitness test.
- 2006
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Ingår i: Occupational Medicine. - : Oxford University Press (OUP). - 0962-7480 .- 1471-8405. ; 56:1, s. 12-17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: No task-based fitness standard currently exists for beach lifeguards (BLGs). AIM: To formulate an easily administered fitness test for BLGs based on the physical demands identified in Phase 1 of the project (previous paper). METHODS: A range of anthropometric and land- and water-based (swimming pool and flume) fitness assessments were administered to 25 male and female volunteer subjects (13 BLGs from the UK). RESULTS: The mean (SD) VO(2max) (l/min) were 3.04 (0.61) for towing a casualty, 2.08 (0.53) for board paddling with a casualty and 2.97 (0.67) for freestyle swimming. A significant correlation (r = -0.82, P < 0.001) was identified between distance paddled in the sea in 3.5 min (established in Phase 1) and pool 400-m front crawl swim time and between towing VO(2max) and deltoid circumference/log(10) 400-m front crawl swim time (r = -0.83, P < 0.001). CONCLUSIONS: The regression identified allows the conclusion that if a BLG can swim 400-m front crawl in a pool in <7.5 min, he/she should be able to paddle 310 m in the sea in <3.5 min. Final recommendations for a fitness test for potential BLGs are presented.
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