Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Clement J. Zablocki VA Medical Center, 5000 West National Avenue, Milwaukee, WI, 53295, USA.
EBioMedicine. 2019 Feb;40:663-674. doi: 10.1016/j.ebiom.2019.01.006. Epub 2019 Feb 8.
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.
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.
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.
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.
常染色体隐性多囊肾病 (ARPKD) 的特征是肾小管中出现囊肿，主要发生在集合管 (CD) 系统中，最终导致终末期肾病。一般建议多囊肾病患者限制其饮食中的钠摄入量。本研究旨在测试 ARPKD 中饮食盐干预的结果。
PCK/CrljCrlPkhd1pck/CRL（PCK）大鼠是 ARPKD 的模型，用正常（0.4% NaCl；NS）、高盐（4% NaCl；HS）和低盐（0.01% NaCl；SD）饮食喂养 8 周。应用免疫组织化学、GFR 测量、平衡研究和分子生物学方法评估方案的结果。用 LC-MS/MS 评估肾素-血管紧张素-醛固酮系统 (RAAS) 水平，研究肾脏 miRNA 谱。
HS 和 SD 饮食均可导致囊肿生成增加。然而，SD 饮食导致肾皮质区域的囊肿广泛生长和组织肥大；SD 组的 RAAS 成分增强。我们观察到 SD 组 ENaC 表达减少，同时伴有 mRNA 水平增加。miRNA 检测显示 SD 组肾脏 miR-9a-5p 水平增加；我们表明该 miRNA 可减少 CD 细胞中的 ENaC 通道数量。
我们的数据表明，盐限制时 ARPKD 进展涉及 ENaC 的活性。我们进一步表明，miR-9a-5p 可能参与了这一机制，miR-9a-5p 在培养的 CD 细胞中下调 ENaC。我们的发现为新的治疗可能性提供了依据，并强调了理解 ARPKD 中盐吸收的重要性。
