Fluid shear stress stimulates MATE2-K expression via Nrf2 pathway activation
Yasunori Fukuda1, Misato Kaishima1, Toshiyuki Ohnishi1
1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan.
Biochemical and Biophysical Research Communications
|January 30, 2017
Summary
Fluid shear stress in kidney proximal tubules influences drug transporter expression via Nrf2 signaling. Microfluidic systems offer a physiologically relevant model for studying drug-induced renal toxicity.
Area of Science:
- Nephrology
- Drug Discovery
- Biotechnology
Background:
- Accurate prediction of drug-induced renal toxicity is crucial for patient safety.
- In vitro assay systems mimicking physiological conditions are needed but challenging to establish.
- Kidney proximal tubules experience fluid shear stress, a factor not fully incorporated into current assays.
Purpose of the Study:
- To investigate the cellular response of human primary proximal tubule cells to fluid shear stress.
- To explore the role of fluid shear stress in regulating drug transporters in the kidney.
- To evaluate microfluidic devices as a model for studying renal toxicity.
Main Methods:
- Utilized microfluidic devices to expose human primary proximal tubule cells to fluid shear stress.
- Analyzed global gene expression profiles under fluidic conditions.
- Performed network and cell biological analyses to understand regulatory mechanisms.
Main Results:
- Fluid shear stress upregulated MATE2-K expression and activated Nrf2 signaling.
- Nrf2 signaling was identified as a regulator of MATE2-K expression.
- Microfluidic culture demonstrated its utility for analyzing gene expression in relevant physiological conditions.
Conclusions:
- Fluid shear stress plays a role in the expression and function of kidney proximal tubule drug transporters.
- Nrf2 signaling mediates the effects of fluid shear stress on MATE2-K.
- Microfluidic systems represent a valuable tool for advancing the study of drug-induced renal toxicity.
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