Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, Nigro M, Gigliotti G. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med. 2025 Feb 13;14(4):1241. doi: 10.3390/jcm14041241. PMID: 40004772; PMCID: PMC11856817.
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.
Conclusions
Several limitations exist that warrant careful consideration. First, uncertainty exists about nephroprotective effects in patients with earlier stages of diabetic nephropathy.
Another notable gap lies in understanding the effects of SGLT2i on endothelial cells and microvascular function. While preclinical studies suggest that SGLT2i may improve endothelial health, by reducing oxidative stress, inflammation, and vascular stiffness, these effects have not been robustly confirmed in human studies. The available data are mostly indirect, inferred from improvements in macrovascular outcomes and reductions in markers like albuminuria. Furthermore, the interplay between SGLT2 inhibition and endothelial repair mechanisms, such as angiogenesis or endothelial progenitor cell function, remains largely unexplored. Given the critical role of endothelial cells in maintaining glomerular integrity and function, this represents a significant knowledge gap.
Future research should address these limitations by conducting studies that specifically evaluate SGLT2i in early stages of diabetic nephropathy. Dedicated trials focusing on the direct effects of SGLT2i on endothelial biomarkers, vascular imaging, and histological studies in kidney tissue are also necessary to elucidate their role in endothelial health.
Further research is warranted to explore the exact molecular mechanisms by which SGLT2i influence endothelial function and to determine how these effects contribute to their overall therapeutic efficacy in diabetic kidney disease.
Although new methods are being developed to interrogate proteinuria and the effects of SGLT2i, understanding these mechanisms mentioned above could lead to the development of more targeted therapies for diabetic nephropathy and other kidney diseases characterized by mitochondrial dysfunction and proteinuria.
Finally, the exploration of endothelial dysfunction and ageing led us to propose a link between endothelial senescence and vascular function, with potential implications for ageing-related kidney disease.
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Keywords:Â SGLT2; ageing-related kidney disease; diabetic nephropathy; endothelial protection; kidney biopsy; mitochondrial function.
