GSTM1 Gene, Diet, and Kidney Disease: Implication for Precision Medicine?: Recent Advances in Hypertension

Abstract

In the United States, the prevalence of chronic kidney disease in adults is ≈14%. The mainstay of therapy for chronic kidney disease is angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, but many patients with chronic kidney disease still progress to end-stage kidney disease. Increased oxidative stress is a major molecular underpinning of chronic kidney disease progression. In humans, a common deletion variant of the glutathione-S-transferase μ-1 (GSTM1) gene, the GSTM1 null allele (GSTM1(0)), results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. GSTM1 belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by Nrf2 (nuclear factor erythroid 2-related factor 2). Cruciferous vegetables in general, and broccoli in particular, are rich in glucoraphanin, a precursor of sulforaphane that has been shown to have protective effects against oxidative damage through the activation of Nrf2. This review will highlight recent human and animal studies implicating the role of GSTM1 deficiency in hypertension and kidney disease, and its impact on the effects of cruciferous vegetables on kidney injury and disease progression, illustrating the significance of gene and environment interaction and a potential for targeted precision medicine in the treatment of kidney disease.

Keywords: glutathione transferase; kidney; oxidative stress; precision medicine; prevalence.

Figure 1:. Sulforaphane-Nrf2-GSTM1 pathway in the prevention of kidney disease progression: Gene - diet interaction.

Glucoraphanine in cruciferous vegetables is hydrolyzed to sulforaphane by myrosinase or by gut microbiome. Sulforaphane inhibits the KEAP-1 mediated degradation of Nrf2, allowing Nrf2 to migrate from the cell cytoplasm into the nucleus where it binds to the antioxidant responsive element in the promoter regions of Nrf2 target genes, including GSTM1, thereby increasing their transcription, and hence their activities. The result is a decrease in reactive oxygen species (ROS), reactive aldehydes (RAs), and factors involved in inflammation and kidney injury. In a disease state such as hypertensive kidney disease, those homozygous for the GSTM1 active allele (GSTM1+) have decreased risk of kidney disease progression through the activation of GSTM1 enzyme. While those carrying the GSTM1 null allele (GSTM1(0)) may be at higher risk of disease progression, they could be protected due to increased bioavailability of sulforaphane to enhance Nrf2-mediated transcription of other antioxidant genes. Figure was modified from Reference # . Image of cruciferous vegetables taken from https://www.eatright.org/food/vitamins-and-supplements/nutrient-rich-foods/the-beginners-guide-to-cruciferous-vegetables Image of the kidney taken from https://www.nephrologyspecialistsoftulsa.com/chronic-kidney-disease.php