Apoptosis signal-regulating kinase 1 promotes Ochratoxin A-induced renal cytotoxicity

Rui Liang1, Xiao Li Shen2, Boyang Zhang1

  • 1Laboratory of food safety and molecular biology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, P.R. China.

Scientific Reports
|January 29, 2015
PubMed

Insights

Apoptosis signal-regulating kinase 1 (ASK1) promotes Ochratoxin A (OTA) kidney damage by increasing oxidative stress and apoptosis. Reducing ASK1 levels protects kidney cells from OTA toxicity.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Cell Biology

Background:

  • Ochratoxin A (OTA) causes kidney damage through oxidative stress and apoptosis.
  • Apoptosis signal-regulating kinase 1 (ASK1) is a key regulator of oxidative stress-induced apoptosis.

Purpose of the Study:

  • To investigate the role of ASK1 in OTA-induced renal cytotoxicity.
  • To elucidate the regulatory mechanism of ASK1 in OTA toxicity using a proteomics approach.

Main Methods:

  • RNA interference (RNAi) to knockdown ASK1 in HEK293 cells.
  • iTRAQ-based quantitative proteomics to analyze protein expression changes.
  • Assessment of reactive oxygen species (ROS) generation and mitochondrial membrane potential (Δψm) loss.

Main Results:

  • ASK1 knockdown reduced OTA-induced ROS generation and Δψm loss, protecting cells from apoptosis.
  • 33 and 24 differentially expressed proteins were identified in control and ASK1-knockdown cells, respectively.
  • ASK1 was found to be involved in inhibiting mRNA splicing, nucleotide metabolism, cell cycle, DNA repair, and activating lipid metabolism.

Conclusions:

  • ASK1 plays a critical role in promoting OTA-induced renal cytotoxicity.
  • Targeting ASK1 may offer a protective strategy against OTA nephrotoxicity.

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
9.4K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
9.3K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.5K
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
17.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
5.1K