Abstract: TH-PO0833
Hierarchical Serum, Urinary, and Tissue Proteomic Responses in Salt-Induced Kidney Injury and Differential Actions of the Mineralocorticoid Receptor (MR) Antagonist Esaxerenone
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Manabe, Shohei, Kinki Daigaku Igakubu Daigakuin Igaku Kenkyuka, Sakai, Osaka Prefecture, Japan
- Nakatani, Yoshihisa, Kinki Daigaku Igakubu Daigakuin Igaku Kenkyuka, Sakai, Osaka Prefecture, Japan
- Nakano, Yukihito, Kinki Daigaku Igakubu Daigakuin Igaku Kenkyuka, Sakai, Osaka Prefecture, Japan
- Sono, Yohei, Kinki Daigaku Igakubu Daigakuin Igaku Kenkyuka, Sakai, Osaka Prefecture, Japan
- Arima, Shuji, Kinki Daigaku Igakubu Daigakuin Igaku Kenkyuka, Sakai, Osaka Prefecture, Japan
Background
High-salt loading induces distinct stress responses in glomeruli and proximal tubules, but whether serum and urinary proteomics reflect tissue injury is unclear. We integrated serum, urinary, and tissue proteomics to characterize responses in salt-sensitive hypertension (SSH) and assess esaxerenone (esax)’s effects.
Methods
Six-week-old male Dahl salt-sensitive rats were assigned to control, high-salt diet (HSD; 8% NaCl), or HSD plus esax (1 mg/kg) for 6 weeks. Blood pressure, serum creatinine, and urinary albumin excretion were measured. Serum and urine were analyzed using a DIA-based proteomic workflow complemented by DDA. Glomeruli and proximal tubules were isolated by laser microdissection and analyzed by LC–MS/MS.
Results
After 6 weeks, HSD raised systolic blood pressure, creatinine, and proteinuria above control levels: 186 mmHg, 0.40 mg/dL, and 142 mg/day compared with 137 mmHg, 0.24 mg/dL, and 18.4 mg/day; esax attenuated these to 162 mmHg, 0.28 mg/dL, and 71 mg/day. Serum proteomics showed modest changes, suggesting limited systemic alterations compared with kidney-derived responses. Urinary proteomics revealed activation of mitochondrial stress, apoptosis, complement/immune signaling, ECM–cytoskeleton remodeling, and lysosomal/lipid metabolism. Keratin 35, Cathepsin D, and CD44 reflected tubular organelle stress and were partially improved by treatment. Tissue proteomics demonstrated segment-specific responses. In glomeruli, HSD enhanced complement activation, inflammatory signaling, nuclear stress, and oxidative phosphorylation, while structural proteins were preserved, suggesting functional stress. Esax attenuated these immune-metabolic changes. In proximal tubules, HSD suppressed mitochondrial/metabolic pathways and increased ER stress and CMA-related proteins. NUCB1, Cathepsin D, and Ppt1 were elevated, indicating organelle stress. Esax partly restored mitochondrial/metabolic programs and reduced ER stress and CMA activation.
Conclusion
High-salt loading induced layered stress in serum, urine, and kidney. Glomeruli showed immune-metabolic stress with preserved structure, whereas proximal tubules showed mitochondrial, ER stress, and CMA changes. Esax attenuated glomerular stress and partly improved tubular organelle pathways. Urinary mitochondrial signatures may indicate tubular injury and esaxerenone-mediated renoprotection.
Acknowledgment
We thank the Core Research Facilities, Kindai University Faculty of Medicine, including the Center for Morphological Analysis and the Center for Instrumental Analysis, for their technical assistance and access to research equipment and facilities.
Funding
- Commercial Support – Esaxerenone was provided by Daiichi Sankyo Co., Ltd.