Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney

Hunjoo Ha, Hi Bahl Lee
Nephrology 2005, 10: S7-10
Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Reactive oxygen species (ROS) play a central role in the ECM synthesis and degradation in the glomeruli and tubulointerstitium leading to renal fibrosis. High glucose (HG) induces cellular ROS through protein kinase C (PKC)-dependent activation of NADPH oxidase and through mitochondrial metabolism. ROS thus generated activate signal transduction cascade (PKC, mitogen-activated protein kinases, and janus kinase/signal transducers and activators of transcription) and transcription factors (nuclear factor-kappaB, activated protein-1, and specificity protein-1), up-regulate transforming growth factor-beta1 (TGF-beta1), angiotensin II (Ang II), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) gene and protein expression, and promote formation of advanced glycation end-products (AGE). PKC, TGF-beta1, Ang II, and AGE also induce cellular ROS and signal through ROS leading to enhanced ECM synthesis. NF-kappaB-MCP-1 pathway is activated by ROS and promotes monocyte recruitment and profibrotic process in the kidney. HG- and TGF-beta1-induced PAI-1 up-regulation is mediated by ROS and contribute to ECM accumulation via suppression of plasmin ativity. TGF-beta1-induced myofibroblast transformation of renal tubular epithelial cells (epithelial-mesenchymal transition) is also mediated by ROS and contribute to tubulointerstitial fibrosis. In summary, ROS transduce and amplify glucose signalling in renal cells under high glucose environment and play a critical role in excessive ECM deposition in the diabetic kidney. A better understanding of ROS production and removal will allow more effective therapeutic strategies in diabetic renal and other vascular complications.

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