Kidney Week

Abstract: TH-PO215

Effects of Suppressed Indoxyl Sulfate Production on Kidney Injury-Associated Cardiac Pathogenesis in Sult1a1-Deficient Mice

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Sugiura, Aina, Kumamoto Daigaku Yakugakubu Daigakuin Yakugaku Kyoikubu, Kumamoto, Kumamoto, Japan

Aina Sugiura

• Makise, Kaito, Kumamoto Daigaku Yakugakubu Daigakuin Yakugaku Kyoikubu, Kumamoto, Kumamoto, Japan

Kaito Makise

• Narita, Yuki, Kumamoto Daigaku Byoin Yakuzaibu, Kumamoto, Kumamoto, Japan

Yuki Narita, PhD

• Kakizoe, Yutaka, Kumamoto University Hospital Department of Nephrology, Kumamoto, Kumamoto, Japan

Yutaka Kakizoe, MD, PhD

• Izumi, Yuichiro, Kumamoto University Hospital Department of Nephrology, Kumamoto, Kumamoto, Japan

Yuichiro Izumi, MD, PhD

• Kuwabara, Takashige, Kumamoto University Hospital Department of Nephrology, Kumamoto, Kumamoto, Japan

Takashige Kuwabara, MD, PhD

• Arima, Yuichiro, Kumamoto University Laboratory of Developmental Cardiology, Kumamoto, Kumamoto, Japan

Yuichiro Arima, DrMed

• Tsujita, Kenichi, Kumamoto University Hospital Department of Cardiovascular Medicine, Kumamoto, Kumamoto, Japan

Kenichi Tsujita, DrMed

• Jono, Hirofumi, Kumamoto Daigaku Byoin Yakuzaibu, Kumamoto, Kumamoto, Japan

Hirofumi Jono, PhD

• Saito, Hideyuki, Kumamoto Daigaku Byoin Yakuzaibu, Kumamoto, Kumamoto, Japan

Hideyuki Saito, PhD

Background

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD) and CVD mortality increases as renal function declines. However, no effective medication has been established to prevent the CVD progression in CKD. Therefore, we focused on indoxyl sulfate (IS), a typical sulfo-conjugated uremic toxin, which is exclusively generated in the liver via the metabolic processes by hepatic metabolizing enzymes, CYP2E1/2E6 and Sulfotransferase (Sult)1a1. IS accumulates systemically in CKD patients, thereby being reported as one of the risk factors for developing cardio-renal disease, whereas the mechanism is unclear. Then, Sult1a1-deficient (Sult1a1^-/-) mice were used to examine the pathogenetic role of IS in a model of cardio-renal disease exhibiting both kidney and heart damages. In this study, cardiac pathological alterations in the model mice were investigated whether the restricted production of IS could prevent those.

Methods

C57BL/6J (WT) and Sult1a1^-/- were used to create an ANS model with angiotensin II administration, nephrectomy, and saline drinking. Mice were sacrificed 4 weeks after the treatment, and blood and tissue samples were collected.

Results

In the ANS model, both WT and Sult1a1^-/- showed increased BUN and expression of IL-6 and col1a1 in renal tissue. On the other hand, WT+ANS increased serum IS concentrations, while Sult1a1^-/-+ANS significantly suppressed IS levels (WT vs Sult1a1^-/-: 5.96±2.96μM vs 2.35±1.09μM). WT+ANS showed cardiac hypertrophy, upregulation of BNP, fibrotic markers TGF-βand col1a1, and oxidative stress marker NOX4 in cardiac tissue, whereas Sult1a1^-/-+ANS suppressed them. Furthermore, cardiac tissue fibrosis formation assessed by Sirius Red staining indicated the reduced fibrotic area in Sult1a1^-/-+ANS compared to WT+ANS (WT vs Sult1a1^-/-: 3±2% vs 1.67±2.08%), suggesting that IS could be involved in the cardiac fibrosis as an intervening toxin.

Conclusion

In Sult1a1^-/-, cardiac hypertrophy and fibrosis development in the ANS model were suppressed with a decreased serum IS accumulation. Therefore, suppression of IS accumulation could prevent and attenuate cardiac pathogenetic events in renal failure.