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Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC). EBioMedicine 2019 Feb;40:663-674

Date

02/13/2019

Pubmed ID

30745171

Pubmed Central ID

PMC6413684

DOI

10.1016/j.ebiom.2019.01.006

Scopus ID

2-s2.0-85061112508   14 Citations

Abstract

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.

FINDINGS: 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.

INTERPRETATION: 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.

Author List

Ilatovskaya DV, Levchenko V, Pavlov TS, Isaeva E, Klemens CA, Johnson J, Liu P, Kriegel AJ, Staruschenko A

Authors

Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Alexander V. Staruschenko PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Biomarkers
Cell Line
Cysts
Diet, Sodium-Restricted
Disease Models, Animal
Epithelial Sodium Channels
Histocytochemistry
Kidney Function Tests
Mice
Mice, Transgenic
MicroRNAs
Polycystic Kidney, Autosomal Recessive
RNA Interference
Rats
Sodium Chloride, Dietary