Department of Nephrology, Medical Faculty, Heinrich-Heine University, 40225, Düsseldorf, Germany.
Institute of Cellular and Integrative Physiology, University Clinic Hamburg-Eppendorf, 20246, Hamburg, Germany.
J Mol Med (Berl). 2022 May;100(5):781-795. doi: 10.1007/s00109-022-02184-5. Epub 2022 Apr 22.
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 PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of β-arrestin2 to nephrin. β-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 PKCα with nephrin. PKCα phosphorylates nephrin at threonine residues 1120 and 1125, mediating the binding of β-arrestin2 to nephrin. β-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.
慢性高血糖症，如糖尿病，可能导致肾小球损伤，微量白蛋白尿是早期标志。值得注意的是，即使是急性高血糖症也会在肾小球滤过结构损伤之前增加肾小球通透性。尽管进行了深入的研究，但目前还没有专门的抗蛋白尿治疗方法。因此，深入了解白蛋白尿的分子机制是可取的。p38MAPK 信号通路参与了高血糖诱导的白蛋白尿的发生。然而，导致 p38MAPK 活性增加从而增加通透性和白蛋白尿的机制尚不清楚。最近，我们证明急性高血糖会触发裂孔隔膜关键分子nephrin 的内吞作用，并诱导白蛋白尿。在这里，我们确定 p38MAPK 是高血糖诱导的 nephrin 内吞作用的关键调节因子。激活的 p38MAPK 在丝氨酸 1146 位点磷酸化 nephrin 的 C 端，促进 PKCα 与 nephrin 的相互作用。PKCα 在 threonine 残基 1120 和 1125 处磷酸化 nephrin，介导β-arrestin2 与 nephrin 的结合。β-arrestin2 通过与内吞机制偶联触发 nephrin 的内吞作用，导致肾小球通透性增加。p38MAPK 的药理学抑制可维持 nephrin 的表面表达，并显著减轻白蛋白尿。关键信息：急性高血糖会触发 nephrin 的内吞作用。激活的 p38MAPK 在丝氨酸 1146 位点磷酸化 nephrin 的 C 端，促进 PKCα 与 nephrin 的相互作用。PKCα 在 threonine 残基 1120 和 1125 处磷酸化 nephrin，介导β-arrestin2 与 nephrin 的结合。β-arrestin2 通过与内吞机制偶联触发 nephrin 的内吞作用，导致肾小球滤过膜渗漏。在高血糖条件下，p38MAPK 的药理学抑制可维持 nephrin 的表面表达，并显著减轻白蛋白尿。
