biostudies-literatureIlatovskaya DVAmerican Heart AssociationBLRD VANational Institute of Health grantsNIDDK NIH HHSNCRR NIH HHSNHLBI NIH HHSPKD FoundationBaltimore PKD CenterDepartment of Veteran Affairs663-674https://www.ebi.ac.uk/biostudies/studies/S-EPMC6413684biostudies-literatureUnknown40<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.EBioMedicineSalt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC).PMC641368416EIA26720006 (AS)P30 DK090868T32 HL134643 (CAK)P01 HL116264 (AS)T32 HL134643R00 HL116603221G18a (DVI)I01 BX004024 (AS)R00 DK105160R00 DK105160 (DVI)R35 HL135749I01 BX004024R00 HL116603 (TSP)M01 RR000058DK090868Pavlov TSIsaeva EKlemens CAStaruschenko AJohnson JLevchenko VIlatovskaya DVLiu PKriegel AJfalseSalt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC).<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.2019-01-01T00:00:00Z2019 Feb2025-04-19T19:15:10.535Z2019-08-04T07:12:03ZS-EPMC64136843074517110.1016/j.ebiom.2019.01.006