Abstract: PO1821
Gstm1 Genotype Affects Metabolic Response in Hypertension
Session Information
- Hypertension and CVD: Mechanisms
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Wang, Yves T., University of Rochester Medical Center, Rochester, New York, United States
- Nguyen, Nhu, University of Rochester Medical Center, Rochester, New York, United States
- Le, Thu H., University of Rochester Medical Center, Rochester, New York, United States
Background
Glutathione S-transferases (GSTs) are a family of enzymes that detoxify electrophiles, including products of oxidative stress. In humans, GST μ-1 (GSTM1) has a common null allele variant, GSTM1(0), which has been linked to elevated oxidative stress in pathophysiological conditions and increased risk and/or accelerated progression of a variety of diseases. Recently, we reported that Gstm1 knockout (KO) mice had increased oxidative stress and augmented kidney injury in angiotensin II (Ang II)-induced hypertension (HTN).
Methods
Kidney tissue was obtained from 12-20 week old male wild-type (WT) and Gstm1 knockout (KO) mice at either baseline (no treatment) or following 4 weeks of Ang II-induced HTN via mini-osmotic pump at 1000 ng/kg/min. For each animal, a kidney was excised and snap frozen. For qPCR, mRNA was extracted from an homogenized kidney and used to create cDNA, followed by probing for a panel of 18 Gst genes. For metabolomics, frozen tissue was ground to a fine powder and sent to Metabolon (Morrisville, NC) to obtain a global metabolic profile.
Results
Analysis of qPCR results showed no significant alterations in the expression of Gst genes between WT and KO mice, except for the expected loss of Gstm1 in KO mice. Metabolomics analysis yielded data for 926 metabolites, with expected significant differences due to Ang II treatment particularly in inflammatory and oxidative stress pathways. About 10% of detected metabolites (97) showed genotype-based effects and a further 131 (14%) displayed an interaction between genotype and treatment. Comparing Ang II-treated KO and WT mice, there was a significant increase in metabolite abundance in the methionine and glutathione pathways, including the transsulfuration pathway linking them. Furthermore, there was an increase in carnosine and anserine and a decrease in several lipid peroxidation markers.
Conclusion
The loss of GSTM1 in Ang II-induced HTN did not elicit a significant compensatory upregulation of mRNA of other GSTs. It is likely other antioxidant pathways are upregulated based on the altered metabolite abundances. However, based on previous results in treated KO mice, any compensatory mechanism is insufficient to protect against the oxidative stress-induced kidney damage. Further research should be pursued to elucidate the oxidative stress-related specific substrates of GSTM1 that are not detoxified by other pathways.
Funding
- NIDDK Support