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Use of Enzymatic Biosensors to Quantify Endogenous ATP or H2O2 in the Kidney
Published on: October 12, 2015
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Superoxide increases angiotensin II AT1 receptor function in human kidney-2 cells
Mohammad Saleem1, Indira Pokkunuri1, Mohammad Asghar1
1Pharmacological and Pharmaceutical Sciences Heart and Kidney Institute College of Pharmacy University of Houston TX USA.
FEBS Open Bio
|February 17, 2017
Summary
Superoxide, not hydrogen peroxide, increases angiotensin II type 1 receptor (AT1R) expression in kidney cells by activating the Sp3 transcription factor. This finding clarifies the role of reactive oxygen species in regulating AT1R, impacting renal cell function.
Area of Science:
- Cell Biology
- Molecular Biology
- Renal Physiology
Background:
- The redox-sensitive Sp family transcription factors regulate angiotensin II type 1 receptor (AT1R).
- The precise mechanism of AT1R regulation in renal cells by reactive oxygen species (ROS) remains unclear.
- Distinguishing the roles of superoxide and hydrogen peroxide (H₂O₂) in this process is crucial.
Purpose of the Study:
- To investigate the specific roles of superoxide and H₂O₂ in regulating AT1R in human kidney cells (HK2).
- To determine the involvement of the Sp3 transcription factor in AT1R regulation by ROS.
- To elucidate the functional consequences of ROS-mediated AT1R modulation.
Main Methods:
- Utilized ROS-sensitive probes (dihydroethidium and dichlorodihydro-fluorescein) to assess superoxide and H₂O₂ levels.
- Administered superoxide dismutase (SOD) inhibitor (DETC) and H₂O₂ to HK2 cells.
- Investigated Sp3 transcription factor nuclear accumulation and AT1R mRNA/protein expression.
- Employed Sp3 overexpression and siRNA-mediated depletion.
- Assessed cell surface AT1R levels via biotinylation and immunofluorescence.
- Measured protein kinase C (PKC) activity.
Main Results:
- DETC treatment increased superoxide levels and nuclear Sp3 accumulation, while H₂O₂ did not.
- DETC, but not H₂O₂, significantly upregulated AT1R mRNA and protein levels.
- Sp3 overexpression enhanced AT1R levels, whereas Sp3 depletion reduced them.
- Superoxide mimetic tempol attenuated DETC-induced Sp3 nuclear accumulation and AT1R upregulation.
- DETC treatment increased cell surface AT1R and enhanced Angiotensin II-induced PKC activity, effects blocked by candesartan and tempol.
Conclusions:
- Superoxide, not H₂O₂, is the primary ROS species that upregulates AT1R expression and function in renal cells.
- The Sp3 transcription factor mediates the effect of superoxide on AT1R.
- These findings provide critical insights into the redox regulation of the renin-angiotensin system in kidney physiology.
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