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

Title Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans.
Publication TypeJournal Article
Year of Publication2020
AuthorsGigliotti JC, Tin A, Pourafshar S, Cechova S, Wang YT, Sung S-SJ, Bodonyi-Kovacs G, Cross JV, Yang G, Nguyen N, Chan F, Rebholz CM, Yu B, Grove ML, Grams ME, Köttgen A, Scharpf R, Ruiz P, Boerwinkle E, Coresh JJ
Secondary AuthorsLe TH
JournalJ Am Soc Nephrol
Volume31
Issue1
Pagination102-116
Date Published2020 01
ISSN1533-3450
KeywordsAnimals, Brassicaceae, Diet, Disease Models, Animal, Female, Gene Deletion, Glutathione Transferase, Humans, Male, Mice, Middle Aged, Renal Insufficiency, Chronic, Vegetables
Abstract

BACKGROUND: encodes glutathione S-transferase -1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent 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 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 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 on renal inflammation.

RESULTS: 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 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 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 deletion variant.

CONCLUSIONS: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.

DOI10.1681/ASN.2019050449
Alternate JournalJ Am Soc Nephrol
PubMed ID31727850
PubMed Central IDPMC6935006
Grant ListHHSN268201100008C / HL / NHLBI NIH HHS / United States
R21 HL098941 / HL / NHLBI NIH HHS / United States
R21 DK112087 / DK / NIDDK NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
S10 RR026799 / RR / NCRR NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 DK094907 / DK / NIDDK NIH HHS / United States
T32 DK072922 / DK / NIDDK NIH HHS / United States