The role of hyperglycemia‐evoked intracellular hyaluronan accumulation and its activity on the autophagic and endoplasmic reticulum stress pathways

Abstract Mesangial expansion is a hallmark of diabetic nephropathy (DN) that reduces the area for filtration and leads eventually to sclerosis and renal failure. A phenotypic activation and transient proliferation of the glomerular mesangial cells and a subsequent prominent glomerular infiltration of monocytes and macrophages appear to have a key role in the induction of mesangial matrix expansion, hypercellularity, and the onset of proteinuria. The molecular mechanisms underlying glomerular infiltration and activation by monocytes in DN are still unclear. Our previous studies indicate that aberrant intracellular synthesis of hyaluronan (HA) by hyperglycemic dividing mesangial cells is the central mechanism involved. These studies demonstrated that mesangial cells that divided in hyperglycemia activated synthesis of HA in intracellular compartments and induced endoplasmic reticulum (ER) stress/autophagy to secrete and form a monocyte adhesive extracellular HA matrix. This recruits inflammatory cells and establishes a chronic inflammatory fibrosis process that leads to sclerosis and renal failure. Our perspectives for the role of intracellular HA synthesis, ER stress, and autophagy in diabetic nephropathy are described.