Intestinal Barrier Function Declines During Polycystic Kidney Disease Progression.

Abstract

Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline PKD1 mutations. In the kidney, Pkd1 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 Pkd1 leads to a leaky intestinal epithelial barrier and increased inflammation, prior to rapid cystogenesis. Control and inducible, global Pkd1 knockout (Pkd1KO) mice were euthanized at 3 and 6 months of age (early and late stage) to evaluate kidney disease progression, small and large intestinal integrity, and inflammation. Early-stage Pkd1KO 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 Pkd1KO mice had severely cystic, impaired kidneys with increased expression of integrity markers, tubular injury and inflammation. Intestinal epithelial barrier was leakier in late stage Pkd1KO 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 Pkd1KO compared to flox mice irrespective of age. Overall, kidney injury appears to precede intestinal injury in ADPKD, whereby the intestinal barrier becomes leaky as cystogenesis progresses.