TY - JOUR
T1 - GSTM1 deletion exaggerates kidney injury in experimental mouse models and confers the protective effect of cruciferous vegetables in mice and humans
AU - Gigliotti, Joseph C.
AU - Tin, Adrienne
AU - Pourafshar, Shirin
AU - Cechova, Sylvia
AU - Wang, Yves T.
AU - Sung, Sun sang J.
AU - Bodonyi-Kovacs, Gabor
AU - Cross, Janet V.
AU - Yang, Guang
AU - Nguyen, Nhu
AU - Chan, Fang
AU - Rebholz, Casey
AU - Yu, Bing
AU - Grove, Megan L.
AU - Grams, Morgan E.
AU - Köttgen, Anna
AU - Scharpf, Robert
AU - Ruiz, Phillip
AU - Boerwinkle, Eric
AU - Coresh, Josef
AU - Le, Thu H.
N1 - Publisher Copyright:
Copyright © 2020 by the American Society of Nephrology.
PY - 2020/1
Y1 - 2020/1
N2 - Background GSTM1 encodes glutathione S-transferase m-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.
AB - Background GSTM1 encodes glutathione S-transferase m-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.
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U2 - 10.1681/ASN.2019050449
DO - 10.1681/ASN.2019050449
M3 - Article
C2 - 31727850
AN - SCOPUS:85077225093
SN - 1046-6673
VL - 31
SP - 102
EP - 116
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 1
ER -