Tumor necrosis factor alpha (TNF-α) disrupts Kir4.1 channel expression resulting in müller cell dysfunction in the retina

Iraj Hassan, Qianyi Luo, Sreeparna Majumdar, James M. Dominguez, Julia V. Busik, Ashay D. Bhatwadekar

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

PURPOSE. Diabetic patients often are affected by vision problems. We previously identified diabetic retinopathy (DR) as a disease of clock gene dysregulation. TNF-α, a proinflammatory cytokine, is known to be elevated in DR. Müller cells maintain retinal water homeostasis and K+ concentration via Kir4.1 channels. Notably, Kir4.1 expression is reduced in diabetes; however, the interplay of TNF-α, Kir4.1, and clock genes in Müller cells remains unknown. We hypothesize that the Kir4.1 in Müller cells is under clock regulation, and increase in TNF-α is detrimental to Kir4.1. METHODS. Long-Evans rats were made diabetic using streptozotocin (STZ). Retinal Kir4.1 expression was determined at different time intervals. Rat Müller (rMC-1) cells were transfected with siRNA for Per2 or Bmal1 and in parallel treated with TNF-α (5–5000 pM) to determine Kir4.1 expression. RESULTS. Kir4.1 expression exhibited a diurnal rhythm in the retina; however, with STZinduced diabetes, Kir4.1 was reduced overall. Kir4.1 rhythm was maintained in vitro in clock synchronized rMC-1 cells. Clock gene siRNA-treated rMC-1 exhibited a decrease in Kir4.1 expression. TNF-α treatment of rMCs lead to a profound decrease in Kir4.1 due to reduced colocalization of Kir4.1 channels with synapse-associated protein (SAP97) and disorganization of the actin cytoskeleton. CONCLUSIONS. Our findings demonstrate that Kir4.1 channels possess a diurnal rhythm, and this rhythm is dampened with diabetes, thereby suggesting that the increase in TNF-α is detrimental to normal Kir4.1 rhythm and expression.

Original languageEnglish (US)
Pages (from-to)2473-2482
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number5
DOIs
StatePublished - May 2017

Keywords

  • Circadian
  • Kir4.1
  • Müller cell
  • TNF-alpha

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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