APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
Date
2024-01
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Attention Stats
Abstract
Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
Type
Department
Description
Provenance
Subjects
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Datta, Somenath, Brett M Antonio, Nathan H Zahler, Jonathan W Theile, Doug Krafte, Hengtao Zhang, Paul B Rosenberg, Alec B Chaves, et al. (2024). APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease. The Journal of clinical investigation, 134(5). p. e172262. 10.1172/jci172262 Retrieved from https://hdl.handle.net/10161/30754.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Paul Brian Rosenberg
Deborah Marie Muoio
Deb Muoio is professor in the Departments of Medicine and Pharmacology & Cancer Biology, George Barth Geller Distinguished Professor of Cardiovascular Disease, and Associate Director of the Duke Molecular Physiology Institute (DMPI). She is viewed nationally and internationally as a leader in the fields of diabetes, obesity, exercise physiology, and mitochondrial energy metabolism. Her laboratory investigates mechanisms of metabolic regulation, with emphasis on molecular events that link lifestyle factors such as over nutrition and physical inactivity to metabolic disorders, including obesity, diabetes, and heart failure. Her program features a translational approach that combines work in animal and cell-based models with human studies, using genetic engineering, molecular biology and mass spectrometry-based metabolomics and proteomics as tools to understand the interplay between mitochondrial physiology and cardiometabolic health. Her laboratory developed a sophisticated platform for deep and comprehensive assessment of mitochondrial bioenergetics and energy transduction. Her team is integrating this new platform with metabolomics, proteomics, and metabolic flux analysis to gain insights into mechanisms by which mitochondria modulate insulin action and metabolic resilience. She has published more than 120 papers in prominent journals such as Cell, Cell Metabolism, Circulation, Circulation Research, Diabetes, and JCI Insight. Dr. Muoio’s laboratory has enjoyed longstanding support from the NIDDK and NHLBI.
PhD, University of North Carolina, Chapel Hill, NC
Guofang Zhang
Sarah Elise Nystrom
Sara Elizabeth Miller
Our laboratory specializes in two areas, infectious diseases, particularlyviral diseases, and ultrastructure-function relationships. Electronmicroscopy (EM) is the focus of the investigative techniques and includes preparative methods such as negative staining, thin sectioning, ultracryomicrotomy and immunolabeling of acrylic and frozen sections.
We are especially interested in methods for diagnosing viral illnesses by EM, and are involved in developing better, more sensitive and faster,methods for detection. While molecular techniques for detecting organisms
are very sensitive, they all require specific reagents, and if the correct probe is not determined a priori, the test is negative. EM offers an open view of any viruses or unsuspected organisms that may be present. We make use of concentration and enhancement methods to increase the chances of
detecting viral agents in fluid specimens. Additionally, we have described a method for selecting small focal areas of pathology in tissue by confocal microscopy to be embedded and examined by EM, increasing the
chances of visualizing organisms. Infectious diseases are the leading cause of death worldwide and the third leading cause in the US. With advanced therapies for cancer patients and many patients living longer
with their disease, a whole new population of infectious disease-susceptible patients has emerged. Chemotherapy, radiation, and bone marrow transplantation are permitting longer survival, but cause
immunosuppression and consequently, strange, unusual diseases, such as polyomavirus infections, sometimes in uncommon body sites. We work closely with physicians to detect and monitor the clearance of
polyomavirus infections in bone marrow and kidney transplant patients. We detect food-borne outbreaks on campus, and we test numerous specimens from patients with infectious diseases. We also serve on the Duke Biodefense Team due to our capability to detect and differentiate poxvirus infections
from those of herpesvirus infections rapidly (within minutes).
Several research collaborations are underway. We have worked with Dr. David Pickup on a structural protein that directs intracellular virus particle movement and maturation. A project with Drs. William Parker and
Randal Bollinger, involves looking at microbes and mucous membrane immunity. It concentrates on biofilms in appendix and lower intestine. We are collaborating with Dr. Meta Kuehn on immunostaining bacterial
vesicles possibly containing endotoxin that have been internalized by
human cells. A different project with Drs. Celia LeBranche and Brian Cullen has examined morphological differences in various retrovirus outer membranes. With Dr. Barton Haynes' laboratory, we determined that cells transfected with single retroviral genes produced subviral particles. With Dr. Michael Hauser's lab, we are examining the difference of myotilin concentration in normal muscle and muscle from muscular dystrophy patients. We worked with a postdoctoral student in the laboratory of Dr. Shirish Shinolokar on staining and examining actin and actin-bundling protein by EM. Finally, we train and assist graduate students, post doctoral students and medical residents how to use electron microscopic techniques in their own studies.
James R. Bain
Olga Ilkayeva
Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.
Thomas Charles Becker
Hans-Ewald Hohmeier
Opeyemi Olabisi
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.