SIK2 is involved in the negative modulation of insulin-dependent muller cell survival and implicated in hyperglycemia-induced cell death.

To investigate the role of the serine/threonine kinase SIK2, a member of the salt-inducible kinase (SIK) family, in insulin-dependent cell survival and hyperglycemia-induced cell death in Müller glia.
Expression studies were performed by RT-PCR, immunostaining, Northern blotting, and immunoblotting. Insulin-dependent changes in SIK2 activity were investigated by in vitro kinase assays in MIO-M1 Müller cell line. Akt activation was studied by immunoblotting and cell death by TUNEL assay. The potential role of SIK2 in insulin signaling was explored by overexpression and sh-RNA knock-down approaches. Effects of hyperglycemia were studied in vitro and in vivo in streptozotocin-injected rats.
SIK2 expression was detected throughout adult retina, except for the outer nuclear layer. Insulin stimulation of MIO-M1 cells resulted in a rapid 2-fold increase of SIK2 activity, increased insulin receptor substrate 1 (IRS1)-SIK2 interaction, and reduced cell death. pAkt levels following insulin treatment were modulated by SIK2 activity. Under hyperglycemia, increased SIK2 activity/expression was concomitant to decreased Akt activation and enhanced apoptosis; whereas knockdown of SIK2 under normo- and hyperglycemic conditions resulted in a rapid increase in pAkt levels and blunted cell death. SIK2 overexpression under normoglycemia had an opposite effect. SIK2 activity increased significantly within 2 weeks of induction of hyperglycemia in the rat retina.
Results indicate that SIK2 functions as a negative modulator of the insulin-dependent survival pathway and contributes to hyperglycemia-induced cell death of Müller glia in vitro. Although still hypothetical at this point, our study suggests that SIK2 could serve a similar role during the development of diabetic retinopathy in vivo and that it represents a potential target to control disease progression.
AuthorsGamze Küser-Abali, Ferruh Ozcan, Asli Ugurlu, Avni Uysal, Stefan H Fuss, Kuyas Bugra-Bilge
JournalInvestigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 54 Issue 5 Pg. 3526-37 (May 2013) ISSN: 1552-5783 [Electronic] United States
PMID23599336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • SIK2 protein, rat
  • Age Factors
  • Animals
  • Cell Death (physiology)
  • Cell Line
  • Cell Survival (physiology)
  • Chronic Disease
  • Diabetes Mellitus, Experimental (metabolism, pathology)
  • Diabetic Retinopathy (metabolism, pathology)
  • Gene Silencing
  • Hyperglycemia (metabolism, pathology)
  • In Situ Nick-End Labeling
  • Insulin (metabolism)
  • Insulin Receptor Substrate Proteins (metabolism)
  • Male
  • Neuroglia (cytology, metabolism)
  • Protein-Serine-Threonine Kinases (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Wistar
  • Retina (cytology, metabolism)
  • Signal Transduction (physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: