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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, primarily caused by PKD1 germline mutations. Polycystin-1, PKD1’s encoded protein, is essential to maintain kidney epithelial cell integrity, but its role in the gut has yet to be determined. Considering macrophage infiltration precedes accelerated cyst growth in Pkd1 knockout ( Pkd1KO) mice, and the gut is the body’s largest reservoir of inflammatory cells, we hypothesized that loss of Pkd1 would weaken the intestinal epithelial cell barrier and mount an inflammatory response, potentially preceding kidney damage. Plasma, urine, kidney, and intestines were collected from 11-12 week old male and female conditional Pkd1KO (CAGG-creER; tamoxifen-induced at 5-6 weeks) and flox (control) mice. Plasma was used to measure intestinal permeability as well as monocyte chemoattractant protein-1 (MCP-1) and lipocalin-2 (LCN-2) concentration. Urine was utilized to assess kidney injury, while tissues were used for RT-PCR and histology. Pkd1KO mice had significantly elevated kidney-to-body weight ratio, cyst ratio, and expression of tubular injury markers kidney injury molecule 1 (Kim1) and Lcn2 compared to flox mice. Despite this cellular injury, kidney inflammatory gene expression and urine osmolality did not differ between genotypes. No overt morphological changes were observed in the ileum or colon, nor were there differences in expression of proinflammatory chemokines or cytokines in either tissue. Plasma abundance of MCP-1 and LCN-2 was similar between genotypes. Epithelial permeability in the small and large intestines was significantly decreased in Pkd1KO versus flox mice. Moreover, Pkd1KO mice had a significantly reduced whole gut transit time compared to flox mice. This corresponded with increases in colonic expression of epithelial integrity marker occludin and water channels aquaporin 4 and aquaporin 8 in Pkd1KO mice. Together, these data insinuate that loss of Pkd1 in the intestines leads to a tighter intestinal barrier accompanied by increased water channel expression and gut motility. These findings appear unrelated to inflammatory involvement in early PKD. These studies were supported by NIH T32 DK007545 to RS, R01 DK132028 to TS, and R03 DK119717 to TS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sedaka et al. (Wed,) studied this question.