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Article: Fluid Shear Stress-Induced Changes in Megalin Trafficking Enhance Endocytic Capacity in Proximal Tubule Cells.

Lackner, Emily M / Cowan, Isabella A / Long, Kimberly R / Weisz, Ora A / Shipman, Katherine E

bioRxiv : the preprint server for biology

2024

Abstract: Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multiligand receptors megalin and cubilin play pivotal roles in the endocytic uptake of ... ...

Abstract	Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multiligand receptors megalin and cubilin play pivotal roles in the endocytic uptake of normally filtered proteins in PT cells but also contribute to the uptake of nephrotoxic drugs, including aminoglycosides. We previously demonstrated that opossum kidney (OK) cells cultured under continuous fluid shear stress (FSS) are superior to cells cultured under static conditions in recapitulating essential functional properties of PT cells
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.22.581213
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Article ; Online: Receptor-associated protein impairs ligand binding to megalin and megalin-dependent endocytic flux in proximal tubule cells.

Long, Kimberly R / Rbaibi, Youssef / Kashlan, Ossama B / Weisz, Ora A

American journal of physiology. Renal physiology

2023 Volume 325, Issue 4, Page(s) F457–F464

Abstract: Proximal tubule (PT) cells retrieve albumin and a broad array of other ligands from the glomerular ultrafiltrate. Efficient uptake of albumin requires PT expression of both megalin and cubilin receptors. Although most proteins engage cubilin selectively, ...

Abstract	Proximal tubule (PT) cells retrieve albumin and a broad array of other ligands from the glomerular ultrafiltrate. Efficient uptake of albumin requires PT expression of both megalin and cubilin receptors. Although most proteins engage cubilin selectively, megalin is required to maintain robust flux through the apical endocytic pathway. Receptor-associated protein (RAP) is a chaperone that directs megalin to the cell surface, and recombinant RAP dramatically inhibits the uptake of numerous megalin and cubilin ligands. The mechanism by which this occurs has been suggested to involve competitive inhibition of ligand binding and/or conformational changes in megalin that prevent interaction with ligands and/or with cubilin. To discriminate between these possibilities, we determined the effect of RAP on endocytosis of albumin, which binds to cubilin and megalin receptors with high and low affinity, respectively. Uptake was quantified in opossum kidney (OK) cells and in megalin or cubilin (
MeSH term(s)	Low Density Lipoprotein Receptor-Related Protein-2/genetics ; Low Density Lipoprotein Receptor-Related Protein-2/metabolism ; Ligands ; Albumins/metabolism ; Cell Membrane/metabolism ; Endocytosis/physiology ; Kidney Tubules, Proximal/metabolism
Chemical Substances	Low Density Lipoprotein Receptor-Related Protein-2 ; Ligands ; Albumins
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00165.2023
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Article ; Online: SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake.

Albalawy, Wafaa N / Youm, Elynna B / Shipman, Katherine E / Trull, Keelan J / Baty, Catherine J / Long, Kimberly R / Rbaibi, Youssef / Wang, Xue-Ping / Fagunloye, Olayemi G / White, Katharine A / Jurczak, Michael J / Kashlan, Ossama B / Weisz, Ora A

American journal of physiology. Renal physiology

2024

Abstract: Beyond glycemic control, SGLT2 inhibitors (SGLT2i) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. ... ...

Abstract	Beyond glycemic control, SGLT2 inhibitors (SGLT2i) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00005.2024
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Article ; Online: Modelling normal and nephrotic axial uptake of albumin and other filtered proteins along the proximal tubule.

Edwards, Aurélie / Long, Kimberly R / Baty, Catherine J / Shipman, Katherine E / Weisz, Ora A

The Journal of physiology

2022 Volume 600, Issue 8, Page(s) 1933–1952

Abstract: Recent studies indicate that filtered albumin is retrieved in the proximal tubule (PT) via three pathways: receptor-mediated endocytosis via cubilin (high affinity) and megalin (low affinity), and fluid-phase uptake. Expression of megalin is required to ... ...

Abstract	Recent studies indicate that filtered albumin is retrieved in the proximal tubule (PT) via three pathways: receptor-mediated endocytosis via cubilin (high affinity) and megalin (low affinity), and fluid-phase uptake. Expression of megalin is required to maintain all three pathways, making it challenging to determine their respective contributions. Moreover, uptake of filtered molecules varies between the sub-segments (S1, S2 and S3) that make up the PT. Here we used new and published data to develop a mathematical model that predicts the rates of albumin uptake in mouse PT sub-segments in normal and nephrotic states, and partially accounts for competition by β
MeSH term(s)	Albumins/metabolism ; Animals ; Endocytosis/physiology ; Female ; Humans ; Immunoglobulin G/metabolism ; Kidney Tubules, Proximal/metabolism ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-2/metabolism ; Male ; Mice ; Proteinuria/metabolism
Chemical Substances	Albumins ; Immunoglobulin G ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-2
Language	English
Publishing date	2022-03-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP282885
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Article ; Online: Access to mental health support, unmet need and preferences among adolescents during the first year of the COVID-19 pandemic.

Gorfinkel, Lauren R / Snell, Gaelen / Long, David / Del Casal, Mari / Wu, Judy / Schonert-Reichl, Kimberly / Guhn, Martin / Samji, Hasina

Health promotion and chronic disease prevention in Canada : research, policy and practice

2023 Volume 43, Issue 4, Page(s) 182–190

Abstract: Introduction: The COVID-19 pandemic has had widespread effects on adolescent mental health. However, little is known about support-seeking, unmet need and preferences for mental health care among adolescents.: Methods: The Youth Development ... ...

Title translation	Accès à du soutien en santé mentale, besoins non comblés et préférences en la matière chez les adolescents au cours de la première année de la pandémie de COVID-19.
Abstract	Introduction: The COVID-19 pandemic has had widespread effects on adolescent mental health. However, little is known about support-seeking, unmet need and preferences for mental health care among adolescents. Methods: The Youth Development Instrument (YDI) is a school-administered survey of adolescents (N = 1928, mean age = 17.1, SD = 0.3) across British Columbia, Canada. In this cohort, we assessed the characteristics of accessed mental health supports, prevalence of unmet need and preferences for in-person versus internet-based services. Results: Overall, 40% of adolescents obtained support for mental health, while 41% experienced unmet need. The most commonly accessed supports were family doctors or pediatricians (23.1%) and adults at school (20.6%). The most preferred mode of mental health care was in-person counselling (72.4%), followed by chat-based services (15.0%), phone call (8.1%) and video call (4.4%). The adjusted prevalence of accessing support was elevated among adolescents with anxiety (adjusted prevalence ratio [aPR] = 1.29, 95% CI: 1.10-1.51), those who used alcohol (1.14, 1.01-1.29), gender minorities (1.28, 1.03-1.58) and sexual minorities (1.28, 1.03-1.45). The adjusted prevalence of unmet need was elevated among adolescents with depression (1.90, 1.67-2.18), those with anxiety (1.78, 1.56-2.03), females (1.43, 1.31-1.58), gender minorities (1.45, 1.23-1.70) and sexual minorities (1.15, 1.07-1.23). Conclusion: Adolescents of gender or sexual minority status and those with anxiety were more likely than others to have discussed mental health concerns and also to have reported unmet need. The most common sources of support were primary health care providers and adults at school, while the most and least preferred modes of support were in-person and video call services, respectively.
MeSH term(s)	Adult ; Female ; Humans ; Adolescent ; Mental Health ; Pandemics ; Mental Health Services ; COVID-19/epidemiology ; COVID-19/therapy ; British Columbia/epidemiology
Language	French
Publishing date	2023-01-18
Publishing country	Canada
Document type	Journal Article
ISSN	2368-738X
ISSN (online)	2368-738X
DOI	10.24095/hpcdp.43.4.03
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Article ; Online: Accès à du soutien en santé mentale, besoins non comblés et préférences en la matière chez les adolescents au cours de la première année de la pandémie de COVID-19

Lauren R. Gorfinkel / Gaelen Snell / David Long / Mari del Casal / Judy Wu / Kimberly Schonert-Reichl / Martin Guhn / Hasina Samji

Promotion de la santé et prévention des maladies chroniques au Canada, Vol 43, Iss 4, Pp 201-

2023 Volume 210

Abstract: IntroductionLa pandémie de COVID-19 a eu des effets importants sur la santé mentale des adolescents. Toutefois, on en sait peu sur la recherche de soutien, les besoins non comblés et les préférences des adolescents en matière de soins de santé mentale. ... ...

Abstract	IntroductionLa pandémie de COVID-19 a eu des effets importants sur la santé mentale des adolescents. Toutefois, on en sait peu sur la recherche de soutien, les besoins non comblés et les préférences des adolescents en matière de soins de santé mentale. MéthodologieL’instrument YDI (Youth Development Instrument, ou Instrument de mesure du développement des jeunes) est une enquête menée auprès d’adolescents (N = 1 928; âge moyen = 17,1; écart-type [ET] = 0,3) dans des écoles de la Colombie-Britannique (Canada). Nous avons évalué, dans la cohorte de l’enquête, les caractéristiques des ressources de soutien en santé mentale consultées, la prévalence des besoins non comblés et la préférence pour les services offerts en personne ou les services offerts sur Internet. RésultatsDans l’ensemble, 40 % des adolescents ont déclaré avoir consulté une ressource de soutien en santé mentale et 41 % ont vu leurs besoins non comblés. Les ressources de soutien le plus souvent consultées ont été les médecins de famille ou les pédiatres (23,1 %) et les adultes à l’école (20,6 %). Le mode de prestation de soins de santé mentale préféré par les adolescents était le counseling en personne (72,4 %), suivi par les services offerts par clavardage (15,0 %), par téléphone (8,1 %) et par appel vidéo (4,4 %). La prévalence ajustée de l’accès à du soutien était élevée chez les adolescents souffrant d’anxiété (ratio de prévalence ajusté [RPa] = 1,29; intervalle de confiance [IC] à 95 % : 1,10 à 1,51), les adolescents consommant de l’alcool (RPa = 1,14; IC à 95 % : 1,01 à 1,29), les minorités de genre (RPa = 1,28; IC à 95 % : 1,03 à 1,58) et les minorités sexuelles (RPa = 1,28; IC à 95 % : 1,03 à 1,45). La prévalence ajustée des besoins non comblés était élevée chez les adolescents souffrant de dépression (1,90; IC à 95 % : 1,67 à 2,18), les adolescents souffrant d’anxiété (RPa = 1,78; 1,56 à 2,03), les adolescentes (RPa = 1,43; IC à 95 % : 1,31 à 1,58), les minorités de genre (1,45; IC à 95 % : 1,23 à 1,70) et les minorités sexuelles (RPa = ...
Keywords	Medicine (General) ; R5-920
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Agence de la santé publique du Canada
Document type	Article ; Online
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Article ; Online: Access to mental health support, unmet need and preferences among adolescents during the first year of the COVID-19 pandemic

Lauren R. Gorfinkel / Gaelen Snell / David Long / Mari del Casal / Judy Wu / Kimberly Schonert-Reichl / Martin Guhn / Hasina Samji

Health Promotion and Chronic Disease Prevention in Canada, Vol 43, Iss 4, Pp 182-

2023 Volume 190

Abstract: IntroductionThe COVID-19 pandemic has had widespread effects on adolescent mental health. However, little is known about support-seeking, unmet need and preferences for mental health care among adolescents. MethodsThe Youth Development Instrument (YDI) ... ...

Abstract	IntroductionThe COVID-19 pandemic has had widespread effects on adolescent mental health. However, little is known about support-seeking, unmet need and preferences for mental health care among adolescents. MethodsThe Youth Development Instrument (YDI) is a school-administered survey of adolescents (N = 1928, mean age = 17.1, SD = 0.3) across British Columbia, Canada. In this cohort, we assessed the characteristics of accessed mental health supports, prevalence of unmet need and preferences for in-person versus internet-based services. ResultsOverall, 40% of adolescents obtained support for mental health, while 41% experienced unmet need. The most commonly accessed supports were family doctors or pediatricians (23.1%) and adults at school (20.6%). The most preferred mode of mental health care was in-person counselling (72.4%), followed by chat-based services (15.0%), phone call (8.1%) and video call (4.4%). The adjusted prevalence of accessing support was elevated among adolescents with anxiety (adjusted prevalence ratio [aPR] = 1.29, 95% CI: 1.10–1.51), those who used alcohol (1.14, 1.01–1.29), gender minorities (1.28, 1.03–1.58) and sexual minorities (1.28, 1.03–1.45). The adjusted prevalence of unmet need was elevated among adolescents with depression (1.90, 1.67–2.18), those with anxiety (1.78, 1.56–2.03), females (1.43, 1.31–1.58), gender minorities (1.45, 1.23–1.70) and sexual minorities (1.15, 1.07–1.23). ConclusionAdolescents of gender or sexual minority status and those with anxiety were more likely than others to have discussed mental health concerns and also to have reported unmet need. The most common sources of support were primary health care providers and adults at school, while the most and least preferred modes of support were in-person and video call services, respectively.
Keywords	Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Public Health Agency of Canada
Document type	Article ; Online
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Article ; Online: Phylogeography as a Proxy for Population Connectivity for Spatial Modeling of Foot-and-Mouth Disease Outbreaks in Vietnam.

Gunasekara, Umanga / Bertram, Miranda R / Van Long, Nguyen / Minh, Phan Quang / Chuong, Vo Dinh / Perez, Andres / Arzt, Jonathan / VanderWaal, Kimberly

Viruses

2023 Volume 15, Issue 2

Abstract: ... spatial adjacency is an imperfect measure of connectivity due to long-distance movement, but we often lack ...

Abstract	Bayesian space-time regression models are helpful tools to describe and predict the distribution of infectious disease outbreaks and to delineate high-risk areas for disease control. In these models, structured and unstructured spatial and temporal effects account for various forms of non-independence amongst case counts across spatial units. Structured spatial effects capture correlations in case counts amongst neighboring provinces arising from shared risk factors or population connectivity. For highly mobile populations, spatial adjacency is an imperfect measure of connectivity due to long-distance movement, but we often lack data on host movements. Phylogeographic models inferring routes of viral dissemination across a region could serve as a proxy for patterns of population connectivity. The objective of this study was to investigate whether the effects of population connectivity in space-time regressions of case counts were better captured by spatial adjacency or by inferences from phylogeographic analyses. To compare these two approaches, we used foot-and-mouth disease virus (FMDV) outbreak data from across Vietnam as an example. We identified that accounting for virus movement through phylogeographic analysis serves as a better proxy for population connectivity than spatial adjacency in spatial-temporal risk models. This approach may contribute to design surveillance activities in countries lacking movement data.
MeSH term(s)	Animals ; Foot-and-Mouth Disease/epidemiology ; Vietnam/epidemiology ; Bayes Theorem ; Phylogeography ; Disease Outbreaks
Language	English
Publishing date	2023-01-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15020388
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Article ; Online: Megalin, cubilin, and Dab2 drive endocytic flux in kidney proximal tubule cells.

Rbaibi, Youssef / Long, Kimberly R / Shipman, Katherine E / Ren, Qidong / Baty, Catherine J / Kashlan, Ossama B / Weisz, Ora A

Molecular biology of the cell

2023 Volume 34, Issue 7, Page(s) ar74

Abstract: The kidney proximal tubule (PT) elaborates a uniquely high-capacity apical endocytic pathway to retrieve albumin and other proteins that escape the glomerular filtration barrier. Megalin and cubilin/amnionless (CUBAM) receptors engage Dab2 in these cells ...

Abstract	The kidney proximal tubule (PT) elaborates a uniquely high-capacity apical endocytic pathway to retrieve albumin and other proteins that escape the glomerular filtration barrier. Megalin and cubilin/amnionless (CUBAM) receptors engage Dab2 in these cells to mediate clathrin-dependent uptake of filtered ligands. Knockout of megalin or Dab2 profoundly inhibits apical endocytosis and is believed to atrophy the endocytic pathway. We generated CRISPR/Cas9 knockout (KO) clones lacking cubilin, megalin, or Dab2 expression in highly differentiated PT cells and determined the impact on albumin internalization and endocytic pathway function. KO of each component had different effects on the concentration dependence of albumin uptake as well its distribution within PT cells. Reduced uptake of a fluid phase marker was also observed, with megalin KO cells having the most dramatic decline. Surprisingly, protein levels and distribution of key endocytic proteins were preserved in KO PT cell lines and in megalin KO mice, despite the reduced endocytic activity. Our data highlight specific functions of megalin, cubilin, and Dab2 in apical endocytosis and demonstrate that these proteins drive endocytic flux without compromising the physical integrity of the apical endocytic pathway. Our studies suggest a novel model to explain how these components coordinate endocytic uptake in PT cells.
MeSH term(s)	Animals ; Mice ; Adaptor Proteins, Signal Transducing/metabolism ; Albumins/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Endocytosis/physiology ; Kidney Tubules, Proximal/metabolism ; Low Density Lipoprotein Receptor-Related Protein-2 ; Mice, Knockout ; Receptors, Cell Surface/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Albumins ; Apoptosis Regulatory Proteins ; Dab2 protein, mouse ; intrinsic factor-cobalamin receptor ; Low Density Lipoprotein Receptor-Related Protein-2 ; Receptors, Cell Surface ; Lrp2 protein, mouse
Language	English
Publishing date	2023-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E22-11-0510
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Article ; Online: A model for predicting both breast cancer risk and non-breast cancer death among women > 55 years old.

Schonberg, Mara A / Wolfson, Emily A / Eliassen, A Heather / Bertrand, Kimberly A / Shvetsov, Yurii B / Rosner, Bernard A / Palmer, Julie R / Ngo, Long H

Breast cancer research : BCR

2023 Volume 25, Issue 1, Page(s) 8

Abstract: Background: Guidelines recommend shared decision making (SDM) for mammography screening for women ≥ 75 and not screening women with < 10-year life expectancy. High-quality SDM requires consideration of women's breast cancer (BC) risk, life expectancy, ... ...

Abstract	Background: Guidelines recommend shared decision making (SDM) for mammography screening for women ≥ 75 and not screening women with < 10-year life expectancy. High-quality SDM requires consideration of women's breast cancer (BC) risk, life expectancy, and values but is hard to implement because no models simultaneously estimate older women's individualized BC risk and life expectancy. Methods: Using competing risk regression and data from 83,330 women > 55 years who completed the 2004 Nurses' Health Study (NHS) questionnaire, we developed (in 2/3 of the cohort, n = 55,533) a model to predict 10-year non-breast cancer (BC) death. We considered 60 mortality risk factors and used best-subsets regression, the Akaike information criterion, and c-index, to identify the best-fitting model. We examined model performance in the remaining 1/3 of the NHS cohort (n = 27,777) and among 17,380 Black Women's Health Study (BWHS) participants, ≥ 55 years, who completed the 2009 questionnaire. We then included the identified mortality predictors in a previously developed competing risk BC prediction model and examined model performance for predicting BC risk. Results: Mean age of NHS development cohort participants was 70.1 years (± 7.0); over 10 years, 3.1% developed BC, 0.3% died of BC, and 20.1% died of other causes; NHS validation cohort participants were similar. BWHS participants were younger (mean age 63.7 years [± 6.7]); over 10-years 3.1% developed BC, 0.4% died of BC, and 11.1% died of other causes. The final non-BC death prediction model included 21 variables (age; body mass index [BMI]; physical function [3 measures]; comorbidities [12]; alcohol; smoking; age at menopause; and mammography use). The final BC prediction model included age, BMI, alcohol and hormone use, family history, age at menopause, age at first birth/parity, and breast biopsy history. When risk factor regression coefficients were applied in the validation cohorts, the c-index for predicting 10-year non-BC death was 0.790 (0.784-0.796) in NHS and 0.768 (0.757-0.780) in BWHS; for predicting 5-year BC risk, the c-index was 0.612 (0.538-0.641) in NHS and 0.573 (0.536-0.611) in BWHS. Conclusions: We developed and validated a novel competing-risk model that predicts 10-year non-BC death and 5-year BC risk. Model risk estimates may help inform SDM around mammography screening.
MeSH term(s)	Pregnancy ; Female ; Humans ; Aged ; Middle Aged ; Breast Neoplasms/diagnosis ; Breast Neoplasms/epidemiology ; Breast Neoplasms/etiology ; Breast ; Risk Factors ; Women's Health ; Mammography
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-023-01605-8
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