Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy

Abstract

Retinopathy and nephropathy are life-threatening diabetic complications that decrease patient quality of life. Although the mechanisms underlying these conditions have been extensively studied, they remain unknown. Recent reports have demonstrated the presence of sodium glucose cotransporter 2 (SGLT2) in retinal pericytes and mesangial cells. Hyperglycemia results in functional and morphological changes in these cells, but these effects are attenuated by phlorizin, a nonselective SGLT inhibitor. Based on these findings, we hypothesized that SGLT2 plays a pivotal role in the development of diabetic nephropathy and retinopathy and that SGLT2 inhibitors may directly protect against these complications.

Keywords: diabetic nephropathy; diabetic retinopathy; mesangial cell; retinal pericytes; sodium glucose cotransporter 2.

Fig. 1.

The glucose uptake thorough glucose transporters in mesangial cells and pericytes. In mesenchymal cells, such as mesangial cells and pericytes, which possess SGLT2 and GLUT1, glucose is only transported into the cells, promoting accumulation of glucose and its metabolites. The ratio of glucose uptake through SGLT2 and GLUT1 is 1:1. Because epithelial cells exhibit cellular polarity, glucose enters the cell via SGLT and is excreted from the cell via GLUT (figure not shown). Since the directions of glucose movement are different between mesenchymal cells such as mesangial cells and pericytes, and epithelial cells such as renal and intestinal epithelial cells, glucose accumulation in the cells may vary between mesenchymal cells and epithelial cells.

Fig. 2.

The mechanism of regulation of glucose-dependent cellular tonicity, cellular swelling and loss of mesangial cells and retinal pericytes. Na⁺ entry via SGLT2 depends on extracellular glucose concentrations and results in Ca²⁺ influx via Sodium-calcium exchanger (NCX), which regulates cellular contraction of mesangial cells and retinal pericytes. This glucose-dependent cellular tonicity disappears after 72 h, and both types of cells begin to swell and are lost due to Na⁺ accumulation under high-glucose conditions since sorbitol and PKC, both of which are derived from excessive intracellular glucose, inhibit () Na⁺-K⁺ ATPase.

Fig. 3.

The mechanism of overproduction of the extracellular matrix in mesangial cells and retinal pericytes. The excessive glucose entered through SGLT2 and GLUT1 activate the diacyl glycerol (DAG)-protein kinase C (PKC)-transforming growth factor β (TGF-β) pathway, which induce overproduction of the extracellular matrices. The inhibition of glucose entry through SGLT2 by SGLT2 inhibitors and phlorizin under high-glucose conditions leads to normalization of intracellular glucose and its metabolites, such as sorbitol and DAG, leading to the inactivation of the DAG-PKC-TGF-β pathway. The normalization of TGF-β activity under high-glucose conditions attenuates the overproduction of extracellular matrices, such as Type IV collagen.