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Review
. 2021 Apr 22;22(9):4374.
doi: 10.3390/ijms22094374.

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

Tomoaki Takata  1 , Hajime Isomoto  1
Affiliations
Review

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

Tomoaki Takata et al. Int J Mol Sci. .

Abstract

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.

Keywords: blood pressure; diabetic kidney disease; diabetic nephropathy; endoplasmic reticulum stress; lipotoxicity; mitochondria; sodium-glucose cotransporter; steatonephropathy; tubuloglomerular feedback; uric acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of the potential mechanisms underlying the renoprotective effect of SGLT2 inhibitors. SGLT2 inhibitors potentially protect the progression of diabetic kidney disease through pleiotropic effects. SGLT2; sodium-glucose cotransporter-2.
Figure 2
Figure 2
Mechanism of SGLT2 inhibition and the regulation of tubuloglomerular feedback. Inhibition of SGLT2 indirectly suppresses the activity of NHE3, leading to increased Na+ delivery to the distal part of the nephron. The elevation of Na+ concentration and increased luminal flow activate the tubuloglomerular feedback and decrease intraglomerular pressure. SGLT2; sodium-glucose cotransporter-2, NHE3; Na+/H+ exchanger 3.
Figure 3
Figure 3
Schematic of lipotoxicity-related ER stress. Ectopic lipid deposition induces ER stress. Excessive ER stress is sensed by three different mediators, namely ATF6, PERK, and IRE1, resulting in cellular apoptosis. GRP78, glucose-regulated protein-78; ATF, activating transcription factor; PERK, PKR-like endoplasmic reticulum kinase; IRE1, inositol requiring 1; and CHOP, C/EBP homologous protein.
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