Kidney Week

Abstract: FR-PO0670

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

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Qiu, Jiahe, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Jiahe Qiu, MS, PhD

• Menezes, Luis F., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Luis F. Menezes, MD, PhD

• Zhou, Fang, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Fang Zhou

• Germino, Gregory G., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Gregory G. Germino, MD

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+ Pkd1^cko/cko; Itgb1^cko/cko compared to Pkd1^cko/cko; Itgb1^cko/wt littermates (2.9% vs 4.1%; p < 0.05) and to Pkd1^cko/cko; Itgb1^wt/wt historic controls (2.9% vs. 3.9%, p<0.01). In contrast, nuclear YAP localization was greatly reduced in Itgb1^cko/cko; Pkd1^cko/cko;Ksp-Cre+ mice (22.44% ± 11.75%) compared to Itgb1^wt/wt Pkd1^cko/cko;Ksp-Cre+ mice (85.50% ± 8.27%) and Itgb1^cko/wt; Pkd1^cko/cko;Ksp-Cre+ (37.31% ± 23.49%). Unexpectedly, KspCre-driven deletion of Itgb1 caused considerable perinatal lethality in Pkd1^cko/wt; Itgb1^cko/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

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025pnn9dr6b