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J Am Soc Nephrol 14:S241-S245, 2003
© 2003 American Society of Nephrology

Supplement Article

Reactive Oxygen Species-Regulated Signaling Pathways in Diabetic Nephropathy

Hi Bahl Lee, Mi-Ra Yu, Yanqiang Yang, Zongpei Jiang and Hunjoo Ha

Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.

Correspondence to Dr. Hunjoo Ha, Hyonam Kidney Laboratory, Soon Chun Hyang University, 657 Hannam-dong, Yongsan-ku, Seoul 140-743, Korea. Phone: +82-2-709-9177, +82-2-792-6657; Fax: +82-2-792-5812;

ABSTRACT. Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney. TGF-{beta}1 has been identified as the key mediator of ECM accumulation in diabetic kidney. High glucose induces TGF-{beta}1 in glomerular mesangial and tubular epithelial cells and in diabetic kidney. Antioxidants inhibit high glucose-induced TGF-{beta}1 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-{beta}1, 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-{kappa}B, activated protein-1, and specificity protein 1) and upregulate TGF-{beta}1 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.kr




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