Abstract P158: Sulforaphane Rich Broccoli Powder Attenuates the Augmented Angiotensin II Induced Renal Inflammation and Injury in GSTM1 Deficient Mice

Abstract

Glutathione- S -transferase μ-1 ( GSTM1 ) enzyme belongs to the superfamily of phase II antioxidant glutathione- S -transferases (GSTs) that are downstream targets of the Nrf2 antioxidant transcription factor. In humans, a common GSTM1 gene deletion variant, the null allele GSTM1(0) , results in decreased or complete absence of GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. We reported that GSTM1(0) is associated with accelerated kidney disease progression in the African Americans Study of Kidney Disease (AASK) participants. To understand the direct impact of GSTM1 deficiency on renal inflammation and oxidative stress, we generated Gstm1 deficient mice (KO) to determine their response to angiotensin II, delivered @ 1000 ng/kg/min for 4 weeks via mini-osmotic pump. Blood pressure (BP) was measured by radiotelemetery. Kidney histopathology was assessed by a renal pathologist blinded to genotype and experimental conditions. Renal leukocyte populations were analyzed quantitatively by flow cytometry. Gstm1 KO mice had significantly higher levels of baseline systolic BP (SBP) and ~ 17 mmHg higher SBP after 4 weeks of Ang II-HTN, compared to WT mice. Gstm1 KO mice have increased renal superoxide levels by nearly 3 folds - independent of activation of Nox2 and Nox4 NADPH oxidases or alteration in superoxide dismutase - and worse kidney injury. These changes were associated with significantly increased renal expression of genes involved in inflammation - chemokine ligand 1 (CXCL-1), monocyte chemotactic protein 1 (MCP-1), Interleukin-1β (IL-1β) and IL-6 ( P <0.05). By flow cytometry, Gstm1 KO mice displayed ~ two fold increases in all leukocyte populations in the kidney, with the exception of the numbers of B cells that were not significantly different between groups. This increased renal inflammation was attenuated by dietary administration of broccoli powder that is rich in sulforaphane, a phytochemical that increases Nrf2 expression, independent of BP. In Ang II-hypertension, loss of GSTM1 enzyme may be deleterious by augmenting oxidative stress and inflammation in the kidney. Stimulation of the Nrf2 pathway in hypertension may be a novel therapeutic approach to prevent kidney disease progression in GSTM1 deficiency.