Signaling Pathways of Podocyte Injury in Diabetic Kidney Disease and the Effect of Sodium-Glucose Cotransporter 2 Inhibitors

Abstract

Diabetic kidney disease (DKD) is one of the most important comorbidities for patients with diabetes, and its incidence has exceeded one tenth, with an increasing trend. Studies have shown that diabetes is associated with a decrease in the number of podocytes. Diabetes can induce apoptosis of podocytes through several apoptotic pathways or induce autophagy of podocytes through related pathways. At the same time, hyperglycemia can also directly lead to apoptosis of podocytes, and the related inflammatory reactions are all harmful to podocytes. Podocyte damage is often accompanied by the production of proteinuria and the progression of DKD. As a new therapeutic agent for diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to be effective in the treatment of diabetes and the improvement of terminal outcomes in many rodent experiments and clinical studies. At the same time, SGLT2i can also play a protective role in diabetes-induced podocyte injury by improving the expression of nephrotic protein defects and inhibiting podocyte cytoskeletal remodeling. Some studies have also shown that SGLT2i can play a role in inhibiting the apoptosis and autophagy of cells. However, there is no relevant study that clearly indicates whether SGLT2i can also play a role in the above pathways in podocytes. This review mainly summarizes the damage to podocyte structure and function in DKD patients and related signaling pathways, as well as the possible protective mechanism of SGLT2i on podocyte function.

Low‑dose ionizing radiation attenuates high glucose‑induced hepatic apoptosis and immune factor release via modulation of a miR‑155‑SOCS1 axis

“…Diabetes may induce apoptosis in multiple types of cells, including podocytes, cardiomyocytes, Schwann cells, and hepatocytes ( 32 – 35 ). In the present study, AML12 cell apoptosis following HG treatment was assessed.…”

Research progress of natural active compounds on improving podocyte function to reduce proteinuria in diabetic kidney disease

“…According to a recent study of Chen et al. [ 110 ], the podocyte injury pathways in DKD are mainly focused on PI3K/AKT signaling pathway, mTOR pathway, JAK/STAT pathway, TGF-β/Smad pathway, Wnt/β-Catenin pathway, MAPK pathway, inflammatory response, oxidative stress, etc. That is similar to our results of NACs on podocytes’ injury, which were almost involved in the regulation of inflammation, oxidative stress and autophagy.…”

Cardiovascular outcomes and safety of SGLT2 inhibitors in chronic kidney disease patients

“…Moreover, the effects of dapagliflozin and canagliflozin can stabilize the changes in patients' levels of triglycerides. This shows that SGLT2 inhibitors can not only lower blood sugar levels but also improve blood pressure and blood lipid levels through the lowering of blood sugar levels (6). It has been shown that SGLT2 inhibitors combined with an angiotensin-converting enzyme inhibitor upregulate the renin-angiotensin system effect in nephropathy, therefore suggesting that blood pressure changes may be influenced by SGLT2 inhibitors (7,8).…”