TGF-ß1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA.

Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-ß1 neutralizing antibody. TGF-ß1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)-52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-ß1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-ß1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.

Hypomagnesemia as a predictor of mortality in hemodialysis patients and the role of proton pump inhibitors: A cross-sectional, 1-year, retrospective cohort study.

Introduction This study aimed to evaluate the association between proton pump inhibitor (PPI) use and serum magnesium levels, and the role of hypomagnesemia and PPI use as a risk factor for mortality in hemodialysis patients. Methods An observational study, including a cross-sectional and 1-year retrospective cohort study. The study comprised 399 hemodialysis patients at a single center, and was conducted from January to September 2014. Multiple linear regression analysis was used to investigate the independent relationship between serum magnesium levels and baseline demographic and clinical variables, including PPI and histamine-2 receptor antagonist use. Cox regression model was used to identify lower serum magnesium level and PPI as a predictor of 1-year mortality. Findings Serum magnesium levels were lower with PPI use than non-PPI use (2.39 ± 0.36 vs. 2.56 ± 0.39 mg/dL, P < 0.001). Multiple linear regression analysis showed that PPI use, low serum albumin levels, and low serum potassium and high-sensitivity C-reactive protein (hs-CRP) levels were significantly associated with low serum magnesium levels. A total of 29 deaths occurred during the follow-up period. According to Cox regression analysis stratified by hs-CRP, only high serum hs-CRP levels (>4.04 mg/L) in association with low serum magnesium levels was an independent risk factor for 1-year mortality (hazard ratio: 2.92; 95% CI: 1.53-6.40, P < 0.001). Discussion Serum magnesium levels are lower in PPI use. In the inflammatory state, a low serum magnesium level is a significant predictor of mortality in hemodialysis patients.