Abstract: SA-PO609
Unveiling Kidney Disease Progression in Autosomal Recessive Polycystic Kidney Disease with Hypertension: Insights from the SS-PCK Rat Model
Session Information
- Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
October 26, 2024 | 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: Cystic
Authors
- Yoshimura, Aya, Fujita Health University, Toyoake, Japan
- Shirozu, Takahiro, Fujita Health University, Toyoake, Japan
- Kugita, Masanori, Fujita Health University, Toyoake, Japan
- Kumamoto, Kanako, Fujita Health University, Toyoake, Japan
- Takizawa, Akiko, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Dwinell, Melinda R., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Hirabayashi, Masumi, National Institute for Physiological Sciences, Okazaki, Japan
- Takahashi, Kazuo, Fujita Health University School of Medicine, Toyoake, Japan
- Aukema, Harold M., University of Manitoba, Winnipeg, Manitoba, Canada
- Yamaguchi, Tamio, Suzuka University of Medical Science, Suzuka, Japan
- Nagao, Shizuko, Fujita Health University, Toyoake, Japan
Background
The SS-PCK rat model offers a novel approach to investigate autosomal recessive polycystic kidney disease (ARPKD) complicated by salt-sensitive hypertension. This model integrates the mutated human orthologous Pkhd1 allele from PCK rats into a Dahl salt-sensitive (SS) background, providing a unique platform to explore the influence of salt sensitivity on cyst formation and renal pathology. Intriguingly, male SS-PCK rats demonstrated significantly elevated blood pressure and renal pathology even under normal salt conditions, presenting distinct medullary cyst formation and reduced renal cyst size compared to PCK rats. Histological examination revealed small cysts in both cortical and medullary regions of SS-PCK kidneys, with renal function parameters declining progressively with age. We examined cellular mechanisms and the effects of an ACE inhibitor.
Methods
PCK and SD rats were obtained from The Jackson Laboratories Japan, Inc, and SS and SS-PCK rats were from Medical College of Wisconsin. Males were given standard chow with a normal salt level. Furthermore, Enalapril was administrated in SS-PCK rats from 5 to 16 weeks of age. Kidney samples were prepared for analytical studies.
Results
Expression analyses indicated decreased levels of Cytochrome P450 4 (Cyp4) family genes, including Cyp4a3 and Cyp4a8, in SS-PCK rats compared to PCK rats, while epithelial sodium channel (ENaC) expressions, specifically β-ENaC and γ-ENaC, were significantly elevated. Additionally, Aquaporin-2 (AQP2) expression was notably higher in SS-PCK rats. Enalapril treatment in SS-PCK rats improved renal function, evidenced by significantly lower serum urea nitrogen and creatinine levels, along with increased Cyp4a1 expression. Furthermore, Enalapril treatment reduced β-ENaC and γ-ENaC expressions, without affecting AQP2 expression.
Conclusion
These findings elucidate the complex mechanisms underlying ARPKD progression, emphasizing the involvement of the Cyp4 signaling pathway and Angiotensin II-induced ENaC expression. Enalapril treatment effectively mitigated hypertension and renal complications, highlighting the therapeutic potential of ACE inhibitors in managing ARPKD and hypertension-associated renal disease.
Funding
- Government Support – Non-U.S.