Intestinal barrier function declines during polycystic kidney disease progression

Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline <i>PKD1</i> mutations. In the kidney, <i>Pkd1</i> 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 <i>Pkd1</i> leads to a leaky intestinal epithelial barrier and increased inflammation, before rapid cystogenesis. Control and inducible, global <i>Pkd1</i> knockout (<i>Pkd1</i>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 <i>Pkd1</i>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 <i>Pkd1</i>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 <i>Pkd1</i>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 <i>Pkd1</i>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.<b>NEW & NOTEWORTHY</b> 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.