Activation of glycogen synthase kinase 3β ameliorates diabetes-induced kidney injury

Meenalakshmi M. Mariappan, Sanjay Prasad, Kristin D'Silva, Esteban Cedillo, Kavithalakshmi Sataranatarajan, Jeffrey L. Barnes, Goutam Ghosh Choudhury, Balakuntalam S. Kasinath

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Abstract

Increase in protein synthesis contributes to kidney hypertrophy and matrix protein accumulation in diabetes. We have previously shown that high glucose-induced matrix protein synthesis is associated with inactivation of glycogen synthase kinase 3β (GSK3β) in renal cells and in the kidneys of diabetic mice. We tested whether activation of GSK3β by sodium nitroprusside (SNP) mitigates kidney injury in diabetes. Studies in kidneyproximal tubular epithelial cells showed that SNP abrogated high glucose-induced laminin increment by stimulating GSK3β and inhibiting Akt, mTORC1, and events in mRNA translation regulated by mTORC1 and ERK. NONOate, an NO donor, also activated GSK3β, indicating that NO may mediate SNP stimulation of GSK3β.SNPadministered for 3weeks to mice with streptozotocin-induced type 1 diabetes ameliorated kidney hypertrophy, accumulation of matrix proteins, and albuminuria without changing blood glucose levels. Signaling studies showed that diabetes and ERK; GSK3β inhibition activated mTORC1 and downstream events in mRNA translation in the kidney cortex. These reactions were abrogated by SNP.Weconclude that activation of GSK3β by SNP ameliorates kidney injury induced by diabetes.

Original languageEnglish (US)
Article numberA19
Pages (from-to)35363-35375
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number51
DOIs
StatePublished - Dec 19 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mariappan, M. M., Prasad, S., D'Silva, K., Cedillo, E., Sataranatarajan, K., Barnes, J. L., Choudhury, G. G., & Kasinath, B. S. (2014). Activation of glycogen synthase kinase 3β ameliorates diabetes-induced kidney injury. Journal of Biological Chemistry, 289(51), 35363-35375. [A19]. https://doi.org/10.1074/jbc.M114.587840