Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC). 2019

Daria V Ilatovskaya, and Vladislav Levchenko, and Tengis S Pavlov, and Elena Isaeva, and Christine A Klemens, and Jessica Johnson, and Pengyuan Liu, and Alison J Kriegel, and Alexander Staruschenko
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

BACKGROUND Autosomal Recessive Polycystic Kidney Disease (ARPKD) is marked by cyst formation in the renal tubules, primarily in the collecting duct (CD) system, ultimately leading to end-stage renal disease. Patients with PKD are generally advised to restrict their dietary sodium intake. This study was aimed at testing the outcomes of dietary salt manipulation in ARPKD. METHODS PCK/CrljCrlPkhd1pck/CRL (PCK) rats, a model of ARPKD, were fed a normal (0.4% NaCl; NS), high salt (4% NaCl; HS), and sodium-deficient (0.01% NaCl; SD) diets for 8 weeks. Immunohistochemistry, GFR measurements, balance studies, and molecular biology approaches were applied to evaluate the outcomes of the protocol. Renin-angiotensin-aldosterone system (RAAS) levels were assessed using LC-MS/MS, and renal miRNA profiles were studied. RESULTS Both HS and SD diets resulted in an increase in cystogenesis. However, SD diet caused extensive growth of cysts in the renal cortical area, and hypertrophy of the tissue; RAAS components were enhanced in the SD group. We observed a reduction in epithelial Na+ channel (ENaC) expression in the SD group, accompanied with mRNA level increase. miRNA assay revealed that renal miR-9a-5p level was augmented in the SD group; we showed that this miRNA decreases ENaC channel number in CD cells. CONCLUSIONS Our data demonstrate a mechanism of ARPKD progression during salt restriction that involves activity of ENaC. We further show that miR-9a-5p potentially implicated in this mechanism and that miR-9a-5p downregulates ENaC in cultured CD cells. Our findings open new therapeutic possibilities and highlight the importance of understanding salt reabsorption in ARPKD.

UI MeSH Term Description Entries
D007677 Kidney Function Tests Laboratory tests used to evaluate how well the kidneys are working through examination of blood and urine. Function Test, Kidney,Function Tests, Kidney,Kidney Function Test,Test, Kidney Function,Tests, Kidney Function
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D003560 Cysts Any fluid-filled closed cavity or sac that is lined by an EPITHELIUM. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Cyst
D004039 Diet, Sodium-Restricted A diet which contains very little sodium chloride. It is prescribed by some for hypertension and for edematous states. (Dorland, 27th ed) Diet, Low-Salt,Diet, Low-Sodium,Diet, Salt-Free,Diet, Low Salt,Diet, Low Sodium,Diet, Salt Free,Diet, Sodium Restricted,Diets, Low-Salt,Diets, Low-Sodium,Diets, Salt-Free,Diets, Sodium-Restricted,Low-Salt Diet,Low-Salt Diets,Low-Sodium Diet,Low-Sodium Diets,Salt-Free Diet,Salt-Free Diets,Sodium-Restricted Diet,Sodium-Restricted Diets
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D006651 Histocytochemistry Study of intracellular distribution of chemicals, reaction sites, enzymes, etc., by means of staining reactions, radioactive isotope uptake, selective metal distribution in electron microscopy, or other methods. Cytochemistry
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune
D017044 Polycystic Kidney, Autosomal Recessive A genetic disorder with autosomal recessive inheritance, characterized by multiple CYSTS in both KIDNEYS and associated LIVER lesions. Serious manifestations are usually present at BIRTH with high PERINATAL MORTALITY. Autosomal Recessive Polycystic Kidney,Autosomal Recessive Polycystic Kidney Disease,Kidney, Polycystic, Autosomal Recessive,Polycystic Kidney Disease, Infantile, Type I,ARPKD,Polycystic Kidney Disease, Autosomal Recessive,Polycystic Kidney Disease, Infantile, Type 1,Polycystic Kidney and Hepatic Disease 1,Polycystic Kidney and Hepatic Disease 1 (Autosomal Recessive)

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