SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy

Abstract

Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.

Keywords: SGLT2; ageing-related kidney disease; diabetic nephropathy; endothelial protection; kidney biopsy; mitochondrial function.

Figure 1

T2DM as a disease of basement membranes (BM). The alteration of endothelial cells induced by advanced glycated products (AGEs) in T2DM is then responsible for the modified composition of the BM. In the case of the glomeruli (left) this causes proteinuria. In the case of other organs the resulting plasma protein escape induces fibrosis and the typical macro and microvascular damages of T2DM (image partially prepared with Biorender).

Figure 2

Effects of SGLT2i and other drugs with nephroprotective effect on hemoglobin.

Figure 3

A conceptual model to explain the efficacy of SGLT2i on endothelial cells A. Normal endothelial cells do not express SGLT2; B. in the presence of stressors the endothelial cells express SGLT2 protein, leading to intracellular accumulation of glucose and Na+ and consequent endothelial dysfunction; C. SGLT2 inhibitors, by inactivating SGLT2 protein, alleviate the accumulation of glucose and Na+ inside endothelial cells.

Figure 4

Relationship between proteinuria (ACR: albumin creatinine ratio) and mitochondrial density in endothelial cells of kidney biopsies. The left panel refers to patients without SGLT2i, whereas right panel describes the biopsies of SGLT2i treated patients. Treatment with SGLT2i modifies the relationship between endothelial mitochondrial activity and proteinuria.