GSTM1-Transsulfuration metabolic axis in kidney disease: therapeutic target in precision medicine - Glutathione-S-transferase μ-1 (GSTM1) belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Homozygous carriers of the GSTM1 null allele, GSTM1(0), are deficient of the enzyme and activity. GSTM1(0) is associated with increased risks of cancer and cardiovascular diseases (CVD). We discovered that GSTM1(0) is associated with more rapid CKD progression in the African American Study of Kidney Disease (AASK) trial participants, independent of and is additive to the effect of the Apolipoprotein L1 (APOL1) high-risk variants. This association has been replicated in the Atherosclerosis Risk in Communities (ARIC) study, and in multiple other populations. While the upstream regulation of GSTM1 has been defined, its downstream effect is poorly understood. Our preliminary data suggest that GSTM1 modulates the balance of hydrogen sulfide (H2S), a gaseous molecule that is an end product of the transsulfuration pathway (TSP) and has emerged as an important regulator of cell metabolism and signaling. We reported that global Gstm1 knockout (KO) mice have increased renal oxidative stress, inflammation and kidney disease in angiotensin II-induced hypertension (Ang II-HTN) and the remnant model of CKD. The mechanism(s) by which deficiency of the ubiquitous GSTM1 enzyme exaggerates renal oxidative stress, inflammation and injury is unknown. Bone marrow cross-transplantation implicated GSTM1 deficiency in the parenchyma rather than bone marrow derived cells drive renal inflammation. Through metabolic profiling, we have strong preliminary data suggesting that GSTM1 modulates the TSP that is critical in maintaining optimal cellular function. Compared to control mice, Gstm1 KO mice have 3-4 fold higher renal levels of the TSP intermediate metabolite cystathionine and significantly decreased levels of H2S, a bioactive end product of the TSP that could be a factor that can explain the phenotypes observed in GSTM1 deficient humans and mice. Moreover, loss of GSTM1 downregulates the activity of cystathionine y-lyase enzyme that generates H2S in the TSP. In AASK, compared to those with GSTM1 active allele, homozygous GSTM1(0) participants with high serum levels of cystathionine were ~ 2 times more likely to have a doubling of serum creatinine or ESRD. Our survival analysis suggests the impact of GSTM1 on the composite outcome in AASK is determined by levels of urinary sulfate, an end product of H2S. We hypothesize that loss of GSTM1 results in lower TSP activity with deleterious impact on CKD states. We will: 1) Test the GSTM1- TSP- H2S axis in Ang II-HTN and CKD models; 2) Test whether GSTM1 informs the vascular-immune and renal epithelial-immune interface effects on renal oxidative stress, inflammation and injury, and dysregulated TSP pathway; and 3) Determine whether H2S levels segregate with GSTM1 genotype and clinical outcomes in CKD Stages 2-5; and leverage our randomized double blind placebo-controlled trial as an external validation of the relationship of H2S and GSTM1, and to test whether sulforaphane, a stimulator of Nrf2, can increase H2S levels in CKD patients in a GSTM1 dependent manner.
