Hyperglycemia and mechanical stress: Targeting the renal podocyte

Abstract

Hyperglycemia and deriving from glomerular hypertension mechanical stress are the key factors underlying pathogenesis of diabetic nephropathy (DN). Multiple direct and secondary effects of both these factors are mediated by complex signaling pathways with extensive interactions. The common signaling pathways stimulated by high glucose and mechanical insult may act in an additive manner, thereby accelerating the cell damage. Podocytes, the cells covering the outer aspect of glomerular basement membrane (GBM), are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Bulging into the Bowman's space, they have no support from the apical side, which makes them particularly susceptible to the effects of mechanical strain. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in GBM, therefore blunting resistance of these cells to mechanical forces. Modulation by these factors of expression and activity of numerous structural and functional proteins results in the (auto)inflammatory responses, dysfunction, apoptosis or necrosis of the podocytes. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. This review summarizes the effects of elevated glucose and mechanical stress that seem to be involved in podocyte impairment in diabetes, with particular focus on the possible interactions between these factors.

Prediabetes and Risk of Glomerular Hyperfiltration and Albuminuria in the General Nondiabetic Population: A Prospective Cohort Study

“…31 However, it remains unclear whether hyperfiltration itself is harmful and what the long-term consequences of hyperfiltration are in prediabetes. We did not find that prediabetes increased the odds ratio of having a mGFR < 60 ml/min/1.73 m 2 after 5.6 years.…”

Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats

“…It is likely that the latter changes may be due to (partly) nondynamic structural alterations in the glomerular filter. In recent years, much focus has been on the role of the decline in podocyte number in diabetic nephropathy, largely paralleling the degree of proteinuria and disease progression (15). Hence, although there is evidence that the ultimate filtration barrier to albumin is not at the podocyte slit diaphragm (17,25), the podocytes are to a very large extent responsible for the maintenance of normal structure and function of the glomerular filter (15).…”

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

“…Although maintaining control of the glycemic index is challenging, it lightens the symptoms of diabetic complications, suggesting that hyperglycemia is the critical induction factor in the development and progression of diabetic complications, including diabetic nephropathy (7,8). Treatment strategies for diabetic nephropathy, such as glycemic and blood pressure control, target various pathways contributing to the development of diabetic nephropathy (9,10).…”