GSTM1 Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans

Joseph C. Gigliotti; Adrienne Tin; Shirin Pourafshar; Sylvia Cechova; Yves T. Wang; Sun-sang J. Sung; Gabor Bodonyi-Kovacs; Janet V. Cross; Guang Yang; Nhu Nguyen; Fang Chan; Casey Rebholz; Bing Yu; Megan L. Grove; Morgan E. Grams; Anna Köttgen; Robert Scharpf; Phillip Ruiz; Eric Boerwinkle; Josef Coresh; Thu H. Le

doi:10.1681/ASN.2019050449

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Visual Abstract

Significance Statement

GSTM1 encodes a member of a superfamily of antioxidant enzymes, and a highly prevalent GSTM1 deletion variant is associated with kidney disease progression in two human study cohorts. In this study, the authors demonstrate that Gstm1 knockout mice exhibit increased oxidative stress, kidney injury, and inflammation in models of CKD and hypertension, and that Gstm1 loss in the parenchyma but not in bone marrow–derived cells drives renal inflammation. Importantly, consumption of broccoli powder or cruciferous vegetables was protective against kidney disease only in Gstm1 knockout mice, and was observed mainly in the human participants in the Atherosclerosis Risk in Communities Study who were homozygous for GSTM1 deletion. These findings suggest that targeting antioxidant therapy specifically in individuals carrying the GSTM1 deletion variant may be effective in delaying kidney disease progression.

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.

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