<i>GSTM1</i> Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans
Gigliotti JC, Tin A, Pourafshar S, Cechova S, Wang YT, Sung SJ, Bodonyi-Kovacs G, Cross JV, Yang G, Nguyen N, Chan F, Rebholz C, Yu B, Grove ML, Grams ME, Köttgen A, Scharpf R, Ruiz P, Boerwinkle E, Coresh J, Le TH
Journal of the American Society of Nephrology : JASN · 33 citations
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
- Intake measured by
- Not stated
Who paid for it
- Funding
- Independent funding
- Government
- Deutsche Forschungsgemeinschaft
- Government
- National Institutes of Health
- Government
- National Heart, Lung, and Blood Institute
- Government
- National Institute of Diabetes and Digestive and Kidney Diseases
- Government
- National Center for Research Resources
- Government
- NHLBI NIH HHS
- Government
- NIDDK NIH HHS
- Government
- German Research Foundation
- Government
- NCRR NIH HHS
- University or hospital
- Coordinated Research Center
- Grants
- National Heart, Lung, and Blood Institute (HHSN268201 100012C); National Heart, Lung, and Blood Institute (HHSN268201100007I); National Heart, Lung, and Blood Institute (HHSN268201100007C); National Heart, Lung, and Blood Institute (HHSN2682 01100008C); National Heart, Lung, and Blood Institute (HH-SN-268201100006C); National Heart, Lung, and Blood Institute (HHSN268201100011C); National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK072922); National Heart, Lung, and Blood Institute (HHSN2682011-00005I); National Heart, Lung, and Blood Institute (HHSN2682011-00009I); National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK094907); National Center for Research Resources (S10 RR026799); National Heart, Lung, and Blood Institute (HHSN268201100005C); National Heart, Lung, and Blood Institute (HHSN268201100005G); National Heart, Lung, and Blood Institute (HHSN268201100010C); Deutsche Forschungsgemeinschaft (KO 3598/3-1); National Heart, Lung, and Blood Institute (HHSN268201100011I); National Heart, Lung, and Blood Institute (HHSN26820 1100009C); National Heart, Lung, and Blood Institute (HHSN2682011-00008I); National Institute of Diabetes and Digestive and Kidney Diseases (R21 DK112087); National Heart, Lung, and Blood Institute (R21 HL098941); National Institutes of Health (R21HL098941)
Based on 10 listed funder(s).
Publication
- Published
- 2019-11-14 · J Am Soc Nephrol · vol. 31 · issue 1 · pp. 102–116
- Publisher
- American Society of Nephrology
- Cited
- 45 citations · more than 83% of similar papers · 1.5× the field average
- References
- 57 works
- Access
- Open access (repository copy)
- Research areas
- Glutathione Transferases and Polymorphisms · Genomics, phytochemicals, and oxidative stress · Endometriosis Research and Treatment
- Keywords
- Kidney disease, Kidney, Medicine, Knockout mouse, Cruciferous vegetables, Internal medicine, Inflammation, Oxidative stress, Endocrinology, Nephropathy, Disease, Physiology, Immunology, Biology, Cancer, Diabetes mellitus, Receptor
- MeSH
- animals, humans, mice, brassicaceae, vegetables, disease models, animal, glutathione transferase, diet, gene deletion, middle aged, female, male, renal insufficiency, chronic
21 authors
From US, DE, CM
- Joseph Christopher GigliottiLiberty University
- Adrienne TinWelch Foundation
- Shirin Pourafshar
- Sylvia Cechova
- Yves T. WangUniversity of Rochester
- Sun‐Sang J. Sung
Abstract
Background
GSTM1 encodes glutathione S-transferase μ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study.
Methods
We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation.
Results
Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant.
Conclusions
Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.
Abstract via Europe PMC. Copyright remains with the authors or publisher.
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