Sedaka Randee, Lovelady Caleb, Hallit Emily, Duyvestyn Branden, Shinde Sejal, Moran-Reyna Aida, Lee Goo, Yamaguchi Shinobu, Maynard Craig L, Saigusa Takamitsu
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Alabama, United States.
Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Alabama, United States.
Am J Physiol Renal Physiol. 2025 Feb 1;328(2):F218-F229. doi: 10.1152/ajprenal.00058.2024. Epub 2024 Dec 18.
Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline mutations. In the kidney, loss impairs epithelial cell integrity and increases macrophage infiltration, contributing to cyst growth. Despite its role as the body's largest inflammatory cell reservoir, it has yet to be elucidated whether a similar phenotype presents in the intestines. We hypothesize that loss of leads to a leaky intestinal epithelial barrier and increased inflammation, before rapid cystogenesis. Control and inducible, global knockout (KO) mice were euthanized at 3 and 6 mo of age (early and late stage) to evaluate kidney disease progression, small and large intestinal integrity, and inflammation. Early-stage KO mice displayed mild cystic kidneys and tubular injury with preserved kidney function. Intestinal epithelial barrier was tighter in KO mice, which was associated with higher expression of cell-cell epithelial integrity markers. However, there was no evidence of local or systemic inflammation in either genotype. Late-stage KO mice had severely cystic, impaired kidneys with increased expression of integrity markers, tubular injury, and inflammation. Intestinal epithelial barrier was leakier in late-stage KO mice, accompanied by gene reduction of integrity markers, increased inflammation, and elevated water and sodium channel expression. Gut motility and fecal water excretion were increased in KO compared with flox mice irrespective of age. Overall, kidney injury appears to precede intestinal injury in ADPKD, whereby the intestinal barrier becomes leaky as cystogenesis progresses. Though autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder, this is the first study to explore a kidney-gut contribution to disease progression. We identified a tightened intestinal epithelial barrier in early PKD, which becomes leaky as kidneys become more cystic, accompanied by a sustained loss of fecal water. Given the only approved ADPKD therapeutic yields adverse aquaretic events, this study emphasizes the need to evaluate extrarenal water loss in patients before prescribing.
大多数常染色体显性多囊肾病（ADPKD）患者因种系突变而出现肾囊肿。在肾脏中，（此处原文缺失关键信息，无法准确翻译）缺失会损害上皮细胞完整性并增加巨噬细胞浸润，从而促进囊肿生长。尽管巨噬细胞作为体内最大的炎症细胞库发挥着作用，但肠道中是否存在类似表型尚待阐明。我们推测，在快速囊肿形成之前，（此处原文缺失关键信息，无法准确翻译）缺失会导致肠道上皮屏障渗漏并增加炎症反应。对对照小鼠和可诱导的全身性（此处原文缺失关键信息，无法准确翻译）基因敲除（KO）小鼠在3个月和6个月龄（早期和晚期）实施安乐死，以评估肾脏疾病进展、小肠和大肠的完整性以及炎症情况。早期KO小鼠表现出轻度肾囊肿和肾小管损伤，但肾功能保持正常。KO小鼠的肠道上皮屏障更紧密，这与细胞间上皮完整性标志物的高表达相关。然而，两种基因型均未出现局部或全身炎症的迹象。晚期KO小鼠患有严重的肾囊肿，肾功能受损，完整性标志物表达增加、肾小管损伤并伴有炎症。晚期KO小鼠的肠道上皮屏障更易渗漏，同时完整性标志物基因表达减少、炎症增加以及水和钠通道表达升高。与flox小鼠相比，无论年龄大小，KO小鼠的肠道蠕动和粪便水排泄均增加。总体而言，在ADPKD中，肾脏损伤似乎先于肠道损伤出现，随着囊肿形成的进展，肠道屏障会变得渗漏。尽管常染色体显性多囊肾病（ADPKD）是一种多系统疾病，但这是首次探索肾脏 - 肠道对疾病进展影响的研究。我们发现早期多囊肾病（PKD）患者的肠道上皮屏障收紧，随着肾脏囊肿增多，该屏障会变得渗漏，并伴有粪便水持续流失。鉴于唯一获批的ADPKD治疗药物会产生不良的水利尿事件，本研究强调在开处方前评估患者肾外失水情况的必要性。
