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

Daria V. Ilatovskaya, Vladislav Levchenko, Tengis S. Pavlov, Elena Isaeva, Christine A. Klemens, Jessica Johnson, Pengyuan Liu, Alison J. Kriegel, Alexander Staruschenko

Research output: Contribution to journalArticlepeer-review

18 Scopus 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.

Original languageEnglish (US)
Pages (from-to)663-674
Number of pages12
JournalEBioMedicine
Volume40
DOIs
StatePublished - Feb 2019
Externally publishedYes

Keywords

  • Autosomal Recessive Polycystic Kidney Disease (ARPKD)
  • Cysts development
  • Epithelial Sodium Channel (ENaC)
  • Renin-angiotensin-aldosterone system (RAAS)
  • Salt diets
  • miR-9a

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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