Kidney Week

Abstract: FR-PO275

Effect of Enalapril in a Novel Human Orthologous Rat Model of Autosomal Recessive Polycystic Kidney Disease With Salt-Sensitive Hypertension

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Yoshimura, Aya, Fujita Health University, Toyoake, Aichi, Japan

Aya Yoshimura,

• Matsuyama, Eriko, Fujita Health University, Toyoake, Aichi, Japan

Eriko Matsuyama,

• Watanabe, Takashi, Fujita Health University, Toyoake, Aichi, Japan

Takashi Watanabe,

• Sakata, Miwa, Fujita Health University, Toyoake, Aichi, Japan

Miwa Sakata,

• Shirozu, Takahiro, Fujita Health University, Toyoake, Aichi, Japan

Takahiro Shirozu,

• Kugita, Masanori, Fujita Health University, Toyoake, Aichi, Japan

Masanori Kugita,

• Kumamoto, Kanako, Fujita Health University, Toyoake, Aichi, Japan

Kanako Kumamoto,

• Takizawa, Akiko, Medical College of Wisconsin, Milwaukee, Wisconsin, United States

Akiko Takizawa,

• Dwinell, Melinda R., Medical College of Wisconsin, Milwaukee, Wisconsin, United States

Melinda R. Dwinell,

• Hirabayashi, Masumi, National Institute for Physiological Sciences, Okazaki, Aichi, Japan

Masumi Hirabayashi,

• Yamaguchi, Tamio, Suzuka University of Medical Science, Suzuka, Mie, Japan

Tamio Yamaguchi,

• Takahashi, Kazuo, Fujita Health University, Toyoake, Aichi, Japan

Kazuo Takahashi,

• Nagao, Shizuko, Fujita Health University, Toyoake, Aichi, Japan

Shizuko Nagao,

Background

One of the causes of hypertension in autosomal recessive polycystic kidney disease (ARPKD) is enhanced salt reabsorption in the collecting duct with increased expression of ENaC (Kaimori et al. 2017), which is targeted by the renin receptor in angiotensin II-induced hypertension (Peng et al. 2017). Recently, the SS-PCK novel rat model of ARPKD with salt-sensitive hypertension was established by introducing the pkhd1 gene from the PCK rat onto the Dahl salt-sensitive (SS) background. In the current study, we investigated pathophysiological characteristics of SS-PCK rats, and the effect of ACEI treatment on hypertension and renal disease progression.

Methods

PCK and Sprague Dawley (SD) rats were obtained from Charles River, and SS and SS-PCK rats were from Medical College of Wisconsin. Males were given standard chow with normal salt level. Furthermore, Enalapril was administrated in SS-PCK rats from 5 to 16 weeks of age. Blood pressure, serum urea nitrogen (SUN) and creatinine (Cre) were measured and kidneys were provided for histology (H&E, PAS and sirius red stains), immunohistochemistry (Ki67 and TGF-β) and immunoblotting (α-, β-, γ-ENaC subunits) analyses.

Results

At 18 weeks of age, blood pressure level was higher in SS-PCK rats compared to either PCK, SS or SD rats. Renal expression of ENaC subunits in SS-PCK was higher than in PCK, SS or SD rats. In SS-PCK compared with PCK, Ki67 expression, kidney weight/body weight and cyst area/section were lower, whereas severe glomerular sclerotic area was higher. Enalapril treatment in SS-PCK ameliorated hypertension, renal cyst formation and glomerulosclerosis, with reduction of Cre, SUN, fibrotic area, and expression level of renal ENaC subunits, Ki67 and TGF-β.

Conclusion

Current findings suggest that the novel rat model of ARPKD with salt-sensitive hypertension could be useful to determine the mechanism of disease progression. By using this strain, it is speculated that ACEI may have a therapeutic potential in ARPKD with salt-sensitive hypertension by reducing ENaC expression.

Funding

• Government Support – Non-U.S.