Aryl Hydrocarbon Receptor Deficiency Attenuates Oxidative Stress Related Mesangial Cell Activation and Macrophage Infiltration and Extracellular Matrix Accumulation in Diabetic Nephropathy.
AIMS Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN) Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. In this study, we investigated the role of AhR in the pathophysiological processes of DN using AhR knockout (AhRKO) and pharmacological inhibitor a naphthoflavone mouse models. RESULTS The increased blood glucose, glucose intolerance, MC activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase 2 (COX 2)/prostaglandin E2 (PGE2) lipid peroxidation, oxidative stress, NADPH oxidase activity, and N e carboxymethyllysine (CML, a major advanced glycation end product) in STZ induced diabetic mice. CML showed remarkably increased AhR/COX 2 DNA binding activity, protein DNA interactions, gene regulation, and ECM formation in MCs and renal proximal tubular cells, which could be reversed by siRNA AhR transfection. CML increased AhR nuclear translocation and biological activity in MCs and renal proximal tubular cells could also be effectively attenuated by antioxidants. INNOVATION We elucidate for the first time that AhR plays an important role in MC activation, macrophage infiltration, and ECM accumulation in DN conferred by oxidative stress. CONCLUSIONS AhR regulated COX 2/PGE2 expression and ECM deposition through oxidative stress cascade is involved in the CML triggered MC activation and macrophage infiltration. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic microvascular complications. Antioxid. Redox Signal. 24, 217 231.
Antioxidants redox signaling