ABSTRACT
Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16INK4a-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16INK4a gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Here, we determined whether inhibition of MLL1/WDR5 activity attenuates renal senescence, inflammation, and fibrosis in mice with ischemia reperfusion injury and in cultured rat renal fibroblasts. MM-102 or OICR-9429, both MLL1/WDR5 protein-protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16INK4a in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression. MM-102 attenuated renal fibrosis and inflammation in the kidney of mice with ischemia reperfusion injury. Moreover, in vitro study showed that transforming growth factor-ß1 induced the expression of MLL1, WDR5, H3K4me3, and p16INK4a. Finally, chromatin immunoprecipitation identified the p16INK4a promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation.
Subject(s)
Acute Kidney Injury/drug therapy , Biphenyl Compounds/therapeutic use , Dihydropyridines/therapeutic use , Fibroblasts/drug effects , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Myeloid-Lymphoid Leukemia Protein/antagonists & inhibitors , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Animals , Biphenyl Compounds/pharmacology , Cell Line , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Dihydropyridines/pharmacology , Drug Evaluation, Preclinical , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mice, Inbred C57BL , Myeloid-Lymphoid Leukemia Protein/metabolism , Rats , Renal Insufficiency/prevention & control , Reperfusion Injury/complicationsABSTRACT
Tight blood pressure (BP) control is important for the prevention of cardiovascular disease in hypertensive patients. A cross-sectional study of 2339 patients from 101 clinics and hospitals in Ibaraki Prefecture was performed to evaluate BP control with the patients' current antihypertensive medication. Group A (n=892) included high-risk hypertensive patients with at least one of the following risk factors: diabetes mellitus, chronic kidney disease or a history of myocardial infarction. Group B (n=586) included patients <65 years old and Group C (n=859) included patients ≥65 years old. Both groups B and C included hypertensive patients without the above risk factors. A mean of 1.8±1.0 antihypertensive drugs per patient were prescribed. A total of 35.8% of all patients received monotherapy, 40% received a combination of three therapies and 20.3% received more than three kinds of drugs. The percentage of patients achieving the target BP at the office and at home was significantly higher in Group C than in the other groups (P<0.001). A combination of more than two antihypertensive drugs, including a high dose of either an angiotensin receptor blocker or a calcium channel blocker, was frequently prescribed to Group A to achieve the target office BP. Although the target BP should be lower in Group A (given their comorbidities), the absolute BP value and the number of medications were similar to the other groups. In conclusion, we demonstrated that physicians should treat hypertension more intensively with a combination of more than two antihypertensive drugs, using a high dose to achieve the target BP. In addition, it is important to teach hypertensive patients the clinical importance of monitoring their BP at home and the need to achieve home BP targets.