Abstract: SA-PO760
Altered Transsulfuration Metabolic Pathway Under GSTM1 Deficiency in Hypertension
Session Information
- Hypertension and CVD: Mechanisms
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1503 Hypertension and CVD: Mechanisms
Authors
- Wang, Yves T., University of Rochester Medical Center, Rochester, New York, United States
- Chen, Luojing, University of Rochester Medical Center, Rochester, New York, United States
- Beane, Timothy Jason, 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-transferase μ-1 (GSTM1) belongs to the superfamily of GSTs that are phase II antioxidant enzymes regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). In humans, homozygous carriers of the common GSTM1(0) null allele are deficient of the enzyme and its activity and have increased risks of chronic kidney disease (CKD) progression. Global Gstm1 knockout (KO) mice have increased renal superoxide levels, inflammation, and kidney injury in angiotensin II-induced hypertension (Ang II-HTN). While the upstream regulation of GSTM1 has been delineated, its downstream effects are poorly understood.
Methods
We took a metabolomic approach using the service of Metabolon (Morrisville, NC) to perform unbiased, global metabolic profiles of kidney tissues of wild-type (WT) and Gstm1 KO mice at baseline and after 4 weeks of Ang II-HTN via mini-osmotic pump at 1000 ng/kg/min (n=6/group). For confirmation, targeted metabolomics was performed using an LC-MS/MS in negative ion mode. Total hydrogen sulfide (H2S) levels were measured using the formation of methylene blue method (n≥6/group).
Results
Among the 926 profiled metabolites, levels of several metabolites of the transsulfuration pathway (TSP) and downstream cysteine metabolism were different between WT and Gstm1 KO mice. Targeted analysis of metabolites in and downstream of the TSP showed that cystathionine was significantly increased in KO vs. WT kidneys in both baseline (3.5-fold, p=0.013) and Ang II-HTN (4.3-fold, p=0.001). Metabolites upstream of cystathionine were not different. Downstream metabolites were unchanged at baseline, but were all reduced (log2(KO/WT)<-0.4) in Ang II-HTN, though the differences of individual metabolites were not statistically significant. Levels of H2S, a bioactive end product of the TSP, were significantly reduced in KO kidneys (21.6±2.9 vs. 28.6±4.9 nmol/kidney, p<0.01).
Conclusion
Our preliminary data suggest that GSTM1 modulates the balance of H2S, a gaseous molecule that has emerged as an important modulator of cell metabolism and signaling with pleiotropic effects, including potent anti-oxidant, anti-inflammatory, and vasodilatory functions. Delineation of the impact of GSTM1-TSP-H2S axis in disease states has important therapeutic implications in kidney and cardiovascular diseases in the context of precision and individualized medicine.
Funding
- NIDDK Support