Abstract: SA-OR058
Additive Antihypertensive and Renoprotective Effects of a Mineralocorticoid Receptor Antagonist Combined with an Endothelin Receptor Type A-Selective Antagonist in Salt-Loaded Spontaneously Diabetic Torii Rats
Session Information
- Kidney Disease with Diabetes: Translational Science Breakthroughs
November 08, 2025 | Location: Room 372A, Convention Center
Abstract Time: 05:00 PM - 05:10 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Shirozu, Takahiro, Fujita Health University, Toyoake, Aichi, Japan
- Yoshimura, Aya, Fujita Health University, Toyoake, Aichi, Japan
- Kugita, Masanori, Fujita Health University, Toyoake, Aichi, Japan
- Kumamoto, Kanako, Fujita Health University, Toyoake, Aichi, Japan
- Yatsushiro, Yuriko, CMIC Pharma Science Co., Ltd., Hokuto, Yamanashi, Japan
- Shirakura, Miu, CMIC Pharma Science Co., Ltd., Hokuto, Yamanashi, Japan
- Ohata, Keiichi, CMIC Holdings Co., Ltd., Minato, Tokyo, Japan
- Akie, Yasuki, CMIC Pharma Science Co., Ltd., Hokuto, Yamanashi, Japan
- Yamaguchi, Tamio, Suzuka University of Medical Science, Suzuka, Mie, Japan
- Takahashi, Kazuo, Fujita Health University, Toyoake, Aichi, Japan
- Nagao, Shizuko, Fujita Health University, Toyoake, Aichi, Japan
Background
Salt-loaded Spontaneously Diabetic Torii (SDT) fatty rats developed diabetic nephropathy with hyporeninemic hypertension and showed limited response to first-line ACE inhibitors. These rats exhibited normal serum aldosterone and salt-induced upregulation of renal endothelin-1 expression. Kerendia (KER), a mineralocorticoid receptor antagonist (MRA), is approved for treating chronic kidney disease in type 2 diabetes. On the other hand, endothelin receptor type A-selective antagonists (ERA) are under development. We investigated the effects of KER combined with the ERA, ambrisentan (AMB) in salt-loaded SDT fatty rats.
Methods
Ten-week-old male SDT fatty rats (n = 20) were assigned to four groups: untreated, 0.3% NaCl, 0.3% NaCl + KER (10 mg/kg/day), and 0.3% NaCl + KER + AMB (5 mg/kg/day). Systolic (SBP) and diastolic blood pressure (DBP) were measured 2 weeks post-treatment. Urine and kidney tissues were collected 3 weeks post-treatment. Urine albumin-to-creatinine ratio (ACR) and liver-type fatty acid binding protein-to-creatinine ratio (L-FABPCR) were analyzed. Kidney tissues were assessed histologically for glomerular and tubular lesions (HE, PAS, Sirius Red) and for relative expression of nephropathy-related genes (Havcr1, Fgb, Fgg, Timp1, A2m, Spp1, Angptl4 and Postn) normalized to Gapdh by qRT-PCR.
Results
Salt loading significantly increased SBP, DBP, ACR, L-FABPCR, and gene expression. KER alone and with AMB significantly reduced SBP, DBP, ACR, and gene expression. L-FABPCR was reduced only by the combination. Histopathological analysis showed tubular atrophy and fibrosis with salt loading, attenuated by KER and AMB. Although exudative glomerular lesions were observed in several rats, no significant difference in incidence was detected between the experimental groups.
Conclusion
MRA provides antihypertensive and renoprotective effects in a salt-loaded SDT fatty rat model of diabetic nephropathy with hyporeninemic hypertension, with additive benefits when combined with ERA.
Funding
- Government Support – Non-U.S.