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

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Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria. / Woznowski, Magdalena Patrycja; Potthoff, Sebastian Alexander; Königshausen, Eva; Haase, Raphael; Hoch, Henning; Meyer-Schwesinger, Catherine; Wiech, Thorsten; Stegbauer, Johannes; Rump, Lars Christian; Sellin, Lorenz; Quack, Ivo.

In: J MOL MED, Vol. 100, No. 5, 05.2022, p. 781-795.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Woznowski, MP, Potthoff, SA, Königshausen, E, Haase, R, Hoch, H, Meyer-Schwesinger, C, Wiech, T, Stegbauer, J, Rump, LC, Sellin, L & Quack, I 2022, 'Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria', J MOL MED, vol. 100, no. 5, pp. 781-795. https://doi.org/10.1007/s00109-022-02184-5

APA

Woznowski, M. P., Potthoff, S. A., Königshausen, E., Haase, R., Hoch, H., Meyer-Schwesinger, C., Wiech, T., Stegbauer, J., Rump, L. C., Sellin, L., & Quack, I. (2022). Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria. J MOL MED, 100(5), 781-795. https://doi.org/10.1007/s00109-022-02184-5

Vancouver

Woznowski MP, Potthoff SA, Königshausen E, Haase R, Hoch H, Meyer-Schwesinger C et al. Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria. J MOL MED. 2022 May;100(5):781-795. https://doi.org/10.1007/s00109-022-02184-5

Bibtex

@article{5a1c87f02263445f853bec47f09ed69b,
title = "Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria",
abstract = "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.",
keywords = "Albuminuria/drug therapy, Endocytosis, Humans, Hyperglycemia/metabolism, Membrane Proteins/metabolism, Podocytes/metabolism, Protein Kinase C-alpha/metabolism, Serine/metabolism, Threonine/metabolism, p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors",
author = "Woznowski, {Magdalena Patrycja} and Potthoff, {Sebastian Alexander} and Eva K{\"o}nigshausen and Raphael Haase and Henning Hoch and Catherine Meyer-Schwesinger and Thorsten Wiech and Johannes Stegbauer and Rump, {Lars Christian} and Lorenz Sellin and Ivo Quack",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = may,
doi = "10.1007/s00109-022-02184-5",
language = "English",
volume = "100",
pages = "781--795",
journal = "J MOL MED",
issn = "0946-2716",
publisher = "Springer",
number = "5",

}

RIS

TY - JOUR

T1 - Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria

AU - Woznowski, Magdalena Patrycja

AU - Potthoff, Sebastian Alexander

AU - Königshausen, Eva

AU - Haase, Raphael

AU - Hoch, Henning

AU - Meyer-Schwesinger, Catherine

AU - Wiech, Thorsten

AU - Stegbauer, Johannes

AU - Rump, Lars Christian

AU - Sellin, Lorenz

AU - Quack, Ivo

N1 - © 2022. The Author(s).

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - Albuminuria/drug therapy

KW - Endocytosis

KW - Humans

KW - Hyperglycemia/metabolism

KW - Membrane Proteins/metabolism

KW - Podocytes/metabolism

KW - Protein Kinase C-alpha/metabolism

KW - Serine/metabolism

KW - Threonine/metabolism

KW - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors

U2 - 10.1007/s00109-022-02184-5

DO - 10.1007/s00109-022-02184-5

M3 - SCORING: Journal article

C2 - 35451598

VL - 100

SP - 781

EP - 795

JO - J MOL MED

JF - J MOL MED

SN - 0946-2716

IS - 5

ER -