phenanthrenes and Albuminuria

MicroRNAs (miRNAs) are involved in multiple biological functions via suppressing target genes. Triptolide is a monomeric compound isolated from a traditional Chinese herb, which exerts protective roles in many kinds of glomerular diseases. However, our understanding of the triptolide effect on miRNAome is still limited. In this study, we found that triptolide significantly decreased albuminuria and improved glomerulosclerosis in rats with diabetic kidney disease (DKD). And triptolide also inhibited extracellular matrix (ECM) protein accumulation and the notch1 pathway activation under diabetic conditions. MiR-137 was significantly decreased in the HG (high glucose)-treated HRMCs and in the kidney tissues of the diabetic rats, but was upregulated by triptolide. In addition, overexpression of miR-137 exerted similar effects to those of triptolide, while miR-137 inhibition aggravated ECM protein accumulation. Luciferase reporter assay results demonstrated that miR-137 directly targets Notch1. Furthermore, the miR-137-dependent effects were due to Notch1 suppression that in turn inhibited ECM protein expression, key mediators of glomerulosclerosis. Finally, downregulation of miR-137 reversed the ECM inhibition role of triptolide in HG cultured HRMCs. Taken together, these findings indicate that triptolide is a potential therapeutic option for DKD and that miR-137/Notch1 pathway play roles in the anti-glomerulosclerosis mechanism of triptolide.

Topics: Albuminuria; Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diet, High-Fat; Diterpenes; Epoxy Compounds; Extracellular Matrix; Gene Expression Regulation; Humans; Kidney; Male; Mesangial Cells; MicroRNAs; Phenanthrenes; Rats, Sprague-Dawley; Receptor, Notch1; Renal Agents; Signal Transduction; Streptozocin; Transfection

In diabetic hypertensive rats, tempol reduces albuminuria by restoring the redox imbalance. Increased formation of reactive oxygen species leading to activation of poly(ADP-ribose) polymerase (PARP)-1 and podocyte loss by apoptosis contribute to albuminuria in diabetes mellitus (DM). In the present study, we investigated the hypothesis that in DM tempol reduces albuminuria by inhibition of PARP-induced podocyte apoptosis.. DM was induced in 4-week-old spontaneously hypertensive rats by streptozotocin. Mouse and human podocyte cell lines were cultured in normal or high-glucose conditions, with or without tempol and/or a PARP-1 inhibitor, PJ34.. In diabetic rats, tempol treatment did not affect plasma glucose levels or systolic blood pressure. Albuminuria was higher in diabetic rats, and it was reduced by tempol. DM leads to an elevation of glomerular apoptotic cells and to podocyte loss; both were prevented by tempol treatment. DM increases the expression of poly(ADP-ribose)-modified proteins in isolated glomeruli, and it was reduced by tempol. In vitro, high glucose increased caspase-3 activity and led to a higher number of apoptotic cells that were prevented by tempol and the PARP-1 inhibitor.. In DM, tempol reduces albuminuria associated with reduction of podocyte apoptosis and decreasing oxidative stress via PARP signaling.

Topics: Albuminuria; Animals; Antioxidants; Apoptosis; Blotting, Western; Caspase 3; Cell Line, Transformed; Cyclic N-Oxides; Diabetes Mellitus, Experimental; Fluorescent Antibody Technique; Humans; Kidney Glomerulus; Male; Membrane Proteins; Mice; Oxidative Stress; Phenanthrenes; Podocytes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Inbred SHR; Signal Transduction; Spin Labels; Streptozocin