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Indoxyl Sulfate and Its Potential Role in Mineralocorticoid Receptor Transactivation in Chronic Kidney Disease

Year: 2024

Type: article

Abstract: BACKGROUND: The uremic toxin indoxyl sulfate (IS) is an important factor in chronic kidney disease (CKD) progression. Inhibitors of the renin-angiotensin system and add-on therapy with mineralocorticoid receptor (MR) antagonists can help reduce proteinuria and suppress CKD progression. However, the association between IS and MR activation remains unknown. MATERIALS AND METHODS: experiments involved transfecting COS-7 cells with MR expression plasmids and MR response element-luciferase reporter plasmids. The cells were then treated with aldosterone (10⁻¹⁰ mol/L), indoxyl sulfate (IS, 500 μmol/L), and α-lipoic acid (10⁻³ mol/L). MR transcriptional activity was investigated by luciferase assays, and protein levels were measured by Western blotting. RESULTS: In the 5/6 nephrectomy model, the serum IS concentration was significantly increased; however, the plasma aldosterone levels were decreased. Immunohistochemistry showed that the expression of IS protein increased in injured tubular cells in the 5/6 nephrectomy group compared with that in the sham group. Furthermore, evaluations of serial kidney sections revealed that the expression site of IS protein was colocalized with the distal nephron, where the expression of MR protein was observed. MR-mediated transcriptional activity in COS-7 cells was increased in an aldosterone concentration-dependent manner. IS increased MR-mediated transcriptional activity and protein levels with and without aldosterone, and α-lipoic acid attenuated this increase. CONCLUSIONS: IS could enhance MR transactivation by increasing MR protein levels through oxidative stress in CKD rats, indicating that treatment with MR antagonists and antioxidants may play a permissive role in inhibiting IS-induced CKD progression.

Source: Cureus

DOI: 10.7759/cureus.75236

Authors: Akiko Kudo, Akihiro Fukuda, Koro Gotoh, Hirotaka Shibata

Institution: Oita University

Language: English

Topic: Hormonal Regulation and Hypertension

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: diamond

Funder: Japan Society for the Promotion of Science