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Effects of diazoxide on streptozotocin induced β cell damage via HSP70/HSP90/TLR4/AMPK signaling pathways

Salih Tunc Kaya1

  • 1Faculty of Arts and Science, Biology Department, Düzce University, Düzce, Turkey.

Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission
|February 6, 2023
PubMed

Insights

Diazoxide protects pancreatic beta cells from streptozotocin (STZ) damage by modulating heat shock proteins and signaling pathways. This mitochondrial potassium channel opener reduces apoptosis and normalizes key protein expressions, offering a potential therapeutic strategy.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Pharmacology

Background:

  • Streptozotocin (STZ) is commonly used to induce pancreatic beta cell damage in vitro, mimicking aspects of diabetes.
  • Pancreatic beta cell dysfunction is a critical factor in diabetes pathogenesis, necessitating research into protective mechanisms.
  • Heat shock proteins (HSP70/HSP90), toll-like receptor 4 (TLR4), and AMP-activated protein kinase (AMPK) are implicated in cellular stress responses and survival.

Purpose of the Study:

  • To investigate the protective effects of diazoxide, a mitochondrial potassium channel opener, against STZ-induced pancreatic beta cell damage.
  • To elucidate the role of HSP70/HSP90, TLR4, and AMPK signaling pathways in mediating diazoxide's protective effects.
  • To evaluate the impact of diazoxide on oxidative stress markers, cell viability, mitochondrial membrane potential, and apoptosis in STZ-treated beta cells.

Main Methods:

  • Utilized the 1.1B4 pancreatic beta cell line exposed to STZ with or without diazoxide.
  • Assessed cell viability, total antioxidant status (TAS), total oxidant status (TOS), and mitochondrial membrane potential (MMP).
  • Quantified protein expression of KATP channel subunits, HSP70, HSP90, TLR4, AMPK, and apoptotic markers (e.g., caspase-3) via Western blotting and TUNEL staining.

Main Results:

  • STZ treatment increased oxidative stress (TOS) and apoptosis (TUNEL-positive cells) while decreasing mitochondrial membrane potential (MMP) and KATP channel expression.
  • Diazoxide did not significantly improve overall oxidative stress or normalize MMP but markedly reduced STZ-induced apoptosis.
  • Diazoxide increased the HSP70:HSP90 ratio and normalized the expression of AMPK, TLR4, KATP channel subunits, and caspase-3 in STZ-treated cells.

Conclusions:

  • Opening of mitochondrial ATP-sensitive potassium (KATP) channels by diazoxide confers protection to pancreatic beta cells against STZ-induced toxicity.
  • The protective mechanism involves the modulation of the HSP70/HSP90/TLR4/AMPK signaling cascade.
  • Diazoxide demonstrates potential as a therapeutic agent for preserving beta cell function in conditions involving oxidative stress and apoptosis.
Keywords:
ATPHSP70HSP90diabetesdiazoxidehumanpotassium channelstreptozotocin

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