TY - JOUR
T1 - Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)
AU - Ilatovskaya, Daria V.
AU - Levchenko, Vladislav
AU - Pavlov, Tengis S.
AU - Isaeva, Elena
AU - Klemens, Christine A.
AU - Johnson, Jessica
AU - Liu, Pengyuan
AU - Kriegel, Alison J.
AU - Staruschenko, Alexander
N1 - Funding Information:
Dr. Ilatovskaya reports grants from National Institute of Health and PKD Foundation. Dr. Pavlov and Dr. Klemens reports grants from National Institute of Health. Mr. Levchenko, Dr. Isaeva, Ms. Johnson, Dr. Liu, and Dr. Kriegel have nothing to disclose. Dr. Staruschenko reports grants from National Institute of Health, Department of Veteran Affairs, and American Heart Association during the conduct of the study; grants from National Institute of Health, Department of Veteran Affairs, American Heart Association, and American Diabetes Association outside the submitted work.
Funding Information:
National Institute of Health grantsR35 HL135749, P01 HL116264 (AS), DK090868 via Baltimore PKD Center and R00 HL116603 (TSP), R00 DK105160 (DVI), T32 HL134643 (CAK), Department of Veteran AffairsI01 BX004024 (AS), PKD Foundation Research grant 221G18a (DVI), and American Heart Association16EIA26720006 (AS).
Funding Information:
National Institute of Health grants R35 HL135749 , P01 HL116264 (AS) , DK090868 via Baltimore PKD Center and R00 HL116603 (TSP) , R00 DK105160 (DVI) , T32 HL134643 (CAK) , Department of Veteran Affairs I01 BX004024 (AS) , PKD Foundation Research grant 221G18a (DVI) , and American Heart Association 16EIA26720006 (AS) .
Publisher Copyright:
© 2019 The Authors
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - Autosomal Recessive Polycystic Kidney Disease (ARPKD)
KW - Cysts development
KW - Epithelial Sodium Channel (ENaC)
KW - Renin-angiotensin-aldosterone system (RAAS)
KW - Salt diets
KW - miR-9a
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U2 - 10.1016/j.ebiom.2019.01.006
DO - 10.1016/j.ebiom.2019.01.006
M3 - Article
C2 - 30745171
AN - SCOPUS:85061112508
VL - 40
SP - 663
EP - 674
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
ER -