Figure 1.

The mechanisms of capillary dysfunction in the heart and kidney and the functional expression of SGLT2 in pericytes and mesangial cells. The functional expression of SGLT2 in pericytes and mesangial cells is increased under diabetic conditions, and the uptake of both glucose and Na⁺ through SGLT2 is also increased. Intracellular sorbitol accumulation and protein kinase C (PKC) activation in response to increased intracellular glucose levels inhibit Na⁺/K⁺-ATPases. Then, intracellular Na⁺ accumulates, which leads to cell swelling and the overproduction of the extracellular matrix (upper panel). These functional changes in pericytes and mesangial cells produce perivascular and interstitial fibrosis. Myocardial fibrosis also occurs, which induces diastolic dysfunction in diabetic cardiomyopathy (DCM). These changes in pericytes and mesangial cells decrease the cellular contractile response and induce capillary structural damage, which promote pericyte loss (pericyte ghosts), microaneurysm formation, capillary occlusion and increased capillary permeability, resulting in peripheral edema (lower panel).