Reactive Oxygen Species-Regulated Signaling Pathways in Diabetic Nephropathy
Top Cited Papers
Open Access
- 1 August 2003
- journal article
- conference paper
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 14 (suppl_3) , S241-S245
- https://doi.org/10.1097/01.asn.0000077410.66390.0f
Abstract
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney. TGF-β1 has been identified as the key mediator of ECM accumulation in diabetic kidney. High glucose induces TGF-β1 in glomerular mesangial and tubular epithelial cells and in diabetic kidney. Antioxidants inhibit high glucose-induced TGF-β1 and ECM expression in glomerular mesangial and tubular epithelial cells and ameliorate features of diabetic nephropathy, suggesting that oxidative stress plays an important role in diabetic renal injury. High glucose induces intracellular reactive oxygen species (ROS) in mesangial and tubular epithelial cells. High glucose-induced ROS in mesangial cells can be effectively blocked by inhibition of protein kinase C (PKC), NADPH oxidase, and mitochondrial electron transfer chain complex I, suggesting that PKC, NADPH oxidase, and mitochondrial metabolism all play a role in high glucose-induced ROS generation. Advanced glycation end products, TGF-β1, and angiotensin II can also induce ROS generation and may amplify high glucose-activated signaling in diabetic kidney. Both high glucose and ROS activate signal transduction cascade (PKC, mitogen-activated protein kinases, and janus kinase/signal transducers and activators of transcription) and transcription factors (nuclear factor-κB, activated protein-1, and specificity protein 1) and upregulate TGF-β1 and ECM genes and proteins. These observations suggest that ROS act as intracellular messengers and integral glucose signaling molecules in diabetic kidney. Future studies elucidating various other target molecules activated by ROS in renal cells cultured under high glucose or in diabetic kidney will allow a better understanding of the final cellular responses to high glucose. E-mail: ha@hkl.ac.krThis publication has 17 references indexed in Scilit:
- Delayed Treatment with Lithospermate B Attenuates Experimental Diabetic Renal InjuryJournal of the American Society of Nephrology, 2003
- Angiotensin II Stimulation of NAD(P)H Oxidase ActivityCirculation Research, 2002
- Phosphorylation of p47phoxSites by PKC α, βΙΙ, δ, and ζ: Effect on Binding to p22phoxand on NADPH Oxidase ActivationBiochemistry, 2002
- PKCζ Regulates TNF-α–Induced Activation of NADPH Oxidase in Endothelial CellsCirculation Research, 2002
- Intracellular Localization and Preassembly of the NADPH Oxidase Complex in Cultured Endothelial CellsJournal of Biological Chemistry, 2002
- Activation of protein kinase C-δ and C-ϵ by oxidative stress in early diabetic rat kidneyAmerican Journal of Kidney Diseases, 2001
- Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucoseKidney International, 2000
- AGEs induce oxidative stress and activate protein kinase C-βIIin neonatal mesangial cellsAmerican Journal of Physiology-Renal Physiology, 2000
- Melatonin and taurine reduce early glomerulopathy in diabetic ratsFree Radical Biology & Medicine, 1999
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)The Lancet, 1998