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, Jahrgang 100, Nr. 5, 05.2022, S. 781-795.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -