Pkd1 and Itgb1 Genetic Interaction Studies Suggest Minor Improvement in Cystic Disease, Pronounced Reduction in YAP Activation in Cysts, and Complex Effects on Itgb1-Associated Perinatal Lethality

Background: The extracellular matrix (ECM) contributes to ADPKD progression, but its mechanistic role remains unclear. Integrin β1 (Itgb1), an ECM receptor critical for cell polarity and downstream epithelial signaling pathways, has been implicated in cystogenesis. Previous work using Aqp2–Cre–driven deletions reported that Itgb1 inactivation nearly prevented Pkd1-associated cystogenesis. Given the profound benefits this afforded, we initiated this study to better understand the functional link between Pkd1 and Itgb1. Methods: We generated single and double mutant mice using Ksp-Cre to target Pkd1 and Itgb1 during nephrogenesis. Survival, genotype distributions, 2 kidney weight/body weight ratios (2KW/BW), and YAP nuclear localization were quantified. T-test or Fisher’s exact test was used for group comparisons. Results: Contrary to prior reports, Itgb1 loss did not suppress cyst formation in Pkd1-deficient mice, though kidney/body weight ratios were modestly reduced in KspCre+ Pkd1cko/cko; Itgb1cko/cko compared to Pkd1cko/cko; Itgb1cko/wt littermates (2.9% vs 4.1%; p < 0.05) and to Pkd1cko/cko; Itgb1wt/wt historic controls (2.9% vs. 3.9%, p<0.01). In contrast, nuclear YAP localization was greatly reduced in Itgb1cko/cko; Pkd1cko/cko;Ksp-Cre+ mice (22.44% ± 11.75%) compared to Itgb1wt/wtPkd1cko/cko;Ksp-Cre+ mice (85.50% ± 8.27%) and Itgb1cko/wt;Pkd1cko/cko;Ksp-Cre+ (37.31% ± 23.49%). Unexpectedly, KspCre-driven deletion of Itgb1 caused considerable perinatal lethality in Pkd1cko/wt; Itgb1cko/cko, which was profoundly mitigated by the homozygous deletion of Pkd1. Conclusion: Our findings confirm a previously reported genetic interaction between Pkd1 and Itgb1, but loss of Itgb1 conferred only limited protection against cystic disease in our model. The protection was accompanied by a pronounced decrease in the nuclear YAP localization observed in Pkd1-mutant cysts. The discordance between the degree of cystic disease protection and nuclear YAP staining reduction suggests that YAP is not a central player in Pkd1-associated cystic disease. The paradoxical rescue of Itgb1 perinatal lethality by Pkd1 homozygous deletion underscores the complex genetic interaction between Pkd1 and Itgb1. Funding: NIDDK Support