Chronic Kidney Disease in Metabolic Disease: Regulation of SGLT2 and Transcriptomic–Epigenetic Effects of Its Pharmacological Inhibition

TL;DR

This paper reviews how SGLT2 inhibitors treat kidney disease by altering gene activity and metabolism in kidney cells.

Contribution

The paper provides a comprehensive review of the molecular and epigenetic effects of SGLT2 inhibition in metabolic kidney disease.

Findings

SGLT2 expression is regulated by metabolic and hormonal pathways in kidney cells.

SGLT2 inhibition reprograms kidney cell metabolism and reduces inflammation.

A single-cell RNA study links SGLT2i therapy to metabolic changes in human kidney cells.

Abstract

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin–angiotensin–aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments.

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