ArticleThe Journal of biological chemistry2011
PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 92 citations in OpenAlex.
- GPR81 Regulates MCT1 Membrane Translocation Through a PKA-Dependent Signaling Pathway in Rat Podocytes.International journal of molecular sciences · 2026Article
- Angiotensin (1-7) exaggerates albuminuria and nephrin gene expression but does not modulate renal function-specific microRNAs expressions in kidneys of db/db mice.Acta diabetologica · 2026Article
- Nicotinamide mononucleotide protects against diabetic nephropathyWorld journal of diabetes · 2025Article
- The Life of a Kidney Podocyte.Acta physiologica (Oxford, England) · 2025Review
- Revisiting nephrin signaling and its specialized effects on the uniquely adaptable podocyte.The Biochemical journal · 2025Review
- GLP-1 and glucagon receptor dual agonism ameliorates kidney allograft fibrosis by improving lipid metabolism.Frontiers in immunology · 2025Article
- T-2 Toxin-Mediated β-Arrestin-1 O-GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Oxidative Stress Contributes to Slit Diaphragm Defects Caused by Disruption of Endocytosis.Kidney international reports · 2024Article
- Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP.Cells · 2023Article
- The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy.Molecules (Basel, Switzerland) · 2022Review
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- Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.JCI insight · 2022Article
- The IRE1α pathway in glomerular diseases: The unfolded protein response and beyond.Frontiers in molecular medicine · 2022Review
- β-Arrestin2 deficiency attenuates oxidative stress in mouse hepatic fibrosis through modulation of NOX4.Acta pharmacologica Sinica · 2021Article
- Nephrotic syndrome in a 7-year-old girl with atypical hemolytic uremic syndrome relapse: Answers.Pediatric nephrology (Berlin, Germany) · 2021Article
- Effects of High Glucose and Lipotoxicity on Diabetic Podocytes.Nutrients · 2021Review
- Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin.Frontiers in physiology · 2021Article
- Phosphorylation of key podocyte proteins and the association with proteinuric kidney disease.American journal of physiology. Renal physiology · 2020Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the β-arrestin2-nephrin interaction by PKCα. We identified PKCα and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCα and led to the formation of a complex of nephrin, PKCα, PICK1, and β-arrestin2 in vitro and in vivo. Binding of β-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCα. Further, cellular knockdown of PKCα and/or PICK1 attenuated the nephrin-β-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCα and PICK1 as promising therapeutic targets for diabetic nephropathy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.