Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria

Chronic hyperglycemia, as in diabetes mellitus, may cause glomerular damage with microalbuminuria as an early sign. Noteworthy, even acute hyperglycemia can increase glomerular permeability before structural damage of the glomerular filter can be detected. Despite intensive research, specific antiproteinuric therapy is not available so far. Thus, a deeper understanding of the molecular mechanisms of albuminuria is desirable. P38 MAPK signaling is involved in the development of hyperglycemia-induced albuminuria. However, the mechanism of increased p38 MAPK activity leading to increased permeability and albuminuria remained unclear. Recently, we demonstrated that acute hyperglycemia triggers endocytosis of nephrin, the key molecule of the slit diaphragm, and induces albuminuria. Here, we identify p38 MAPK as a pivotal regulator of hyperglycemia-induced nephrin endocytosis. Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKC alpha with nephrin. PKC alpha phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of beta-arrestin2 to nephrin. beta-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to increased glomerular permeability. Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria. Key messages Acute hyperglycemia triggers endocytosis of nephrin. Activated p38 MAPK phosphorylates the nephrin c-terminus at serine 1146, facilitating the interaction of PKC alpha with nephrin. PKC alpha phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of beta-arrestin2 to nephrin. beta-arrestin2 triggers endocytosis of nephrin by coupling it to the endocytic machinery, leading to a leaky glomerular filter. Pharmacological inhibition of p38 MAPK preserves nephrin surface expression and significantly attenuates albuminuria under hyperglycemic conditions.

Automated summary

Chronic hyperglycemia, such as in diabetes mellitus, can lead to early signs of glomerular damage with microalbuminuria. Even acute hyperglycemia can increase glomerular permeability before structural damage occurs. A deeper understanding of the molecular mechanisms of albuminuria is desired. P38 MAPK signaling is involved in the development of hyperglycemia-induced albuminuria. Acute hyperglycemia triggers endocytosis of nephrin, the key molecule of the slit diaphragm.