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Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant-related dRTA has been linked with the mis-trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affects intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity, and decreased autophagy and protein degradative flux.
Pubmed ID: 41778592
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Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.
View all literature mentionsThe Canadian Institutes of Health Research (CIHR) is the Government of Canada''s agency responsible for funding health research in Canada. CIHR was created in 2000 under the authority of the CIHR Act and reports to Parliament through the Minister of Health. CIHR''s budget for 2008-09 is $928.6 million, of which $132 million is allocated to administering the Networks of Centres of Excellence and Canada Research Chair programs. CIHR was created to transform health research in Canada by: * funding more research on targeted priority areas; * building research capacity in under-developed areas such as population health and health services research; * training the next generation of health researchers; and * focusing on knowledge translation, so that the results of research are transformed into policies, practices, procedures, products and services. CIHR consists of 13 virtual institutes, a structure that is unique in the world. These innovative institutes bring together all partners in the research process - the people who fund research, those who carry it out and those who use its results - to share ideas and focus on what Canadians need: good health and the means to prevent disease and fight it when it happens. Each institute supports a broad spectrum of research in its topic areas and, in consultation with its stakeholders, sets priorities for research in those areas.
View all literature mentionsNSERC aims to make Canada a country of discoverers and innovators for the benefit of all Canadians. The agency supports university students in their advanced studies, promotes and supports discovery research, and fosters innovation by encouraging Canadian companies to participate and invest in postsecondary research projects. NSERC researchers are on the vanguard of science, building on Canada''s long tradition of scientific excellence.
View all literature mentionsCore provides services, including repair of lab equipment and biosafety cabinets, metal and acrylic fabrication, woodworking, welding, machining, and calibration of pipets.
View all literature mentionsCell Imaging Centre provides services and training for imaging and analysis of live or fixed cells and tissues.Image acquisition equipment and expert consultation for experimental design related to light and electron microscopy are offered, with full technical assistance, from sample processing through image analysis.
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