Journal of the American Society of Nephrology
2007 JASN IMPACT FACTOR 7.111 HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP 
    advanced
CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, H. B.
Right arrow Articles by Ha, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, H. B.
Right arrow Articles by Ha, H.
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
Top
 Abstract
Introduction
 Mechanisms of High Glucose...
 Conclusion
 References
 
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


   Introduction
Top
 Abstract
 Introduction
Mechanisms of High Glucose...
 Conclusion
 References
 
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney, leading to glomerular mesangial expansion and tubulointerstitial fibrosis. Clinical studies (1,2) have demonstrated that high blood glucose is the main determinant of initiation and progression of diabetic vascular complications including nephropathy. High glucose induces reactive oxygen species (ROS) (3,4) and upregulates TGF-{beta}1 (5,6) and ECM (5–7) expression in the glomerular mesangial cells. Exogenous hydrogen peroxide (H2O2) or H2O2 continuously generated by glucose oxidase (GO) also upregulates TGF-{beta}1 and fibronectin expression in mesangial cells (4,8) and fibronectin in tubular epithelial cells (9). Finally, antioxidants effectively inhibit high glucose- and H2O2-induced TGF-{beta}1 and fibronectin upregulation (4,8,9–11), thus providing evidence that ROS play an important role in high glucose-induced renal injury. ROS-regulated signaling pathways leading to final renal cellular responses in diabetic kidney are not entirely clear, however.

In this article, we review the mechanisms of high glucose-induced ROS generation and ROS-induced activation of signal transduction cascade and transcription factors and overexpression of genes and proteins in glomerular mesangial and tubular epithelial cells leading to ECM accumulation in diabetic kidney. We also briefly comment on the mechanisms of ROS generation by advanced glycation end products (AGE), TGF-{beta}1, and angiotensin II (Ang II), which may amplify high glucose-activated signaling in diabetic kidney.


   Mechanisms of High Glucose-Induced ROS Generation
Top
 Abstract
 Introduction
 Mechanisms of High Glucose...
Conclusion
 References
 
We have demonstrated that high glucose induces dichlorofluorescein (DCF)-sensitive ROS in the glomerular mesangial (3) and tubular epithelial (12) cells in a time-dependent manner. 3-O-methyl-D-glucose or L-glucose in the same concentrations as D-glucose failed to induce intracellular ROS in mesangial cells, and cytochalasin B, an inhibitor of glucose transporter, completely inhibited D-glucose-induced intracellular ROS, suggesting that high glucose-induced intracellular ROS depends on glucose uptake and metabolism in mesangial cells (3).

High glucose-induced ROS generation in mesangial cells is effectively blocked by calphostin C, a protein kinase C (PKC) inhibitor, or by depletion of intracellular PKC by preincubating cells with PMA for 24 h (3), suggesting that high glucose-induced ROS generation in mesangial cells is PKC dependent as in aortic smooth muscle and endothelial cells (13). PKC has been shown to play an important role in the activation of both phagocytic and nonphagocytic NADPH oxidase (13–15). NADPH oxidase is accepted as the most important mechanism for receptor-stimulated ROS generation in both phagocytic and nonphagocytic cells (16,17). However, Nishikawa et al. (18) demonstrated that high glucose generates superoxide anion in bovine aortic endothelial cells through mitochondrial metabolism. By normalizing mitochondrial superoxide overproduction, they were able to inhibit the activation of PKC, AGE formation, and increased aldose reductase pathway, suggesting that ROS produced by mitochondria play a critical role in high glucose-induced diabetic vascular complications (18). We observed that NADPH oxidase inhibitors apocynin and diphenylene iodonium (DPI), and an inhibitor of mitochondrial electron transfer chain complex I, rotenone, effectively block high glucose-induced ROS generation in mesangial cells (Figure 1A) and high glucose-induced fibronectin secretion by tubular epithelial cells (Figure 1B), suggesting that both NADPH oxidase system and mitochondrial metabolism are involved. The relative contribution of PKC, NADPH oxidase, and mitochondrial metabolism to high glucose-induced ROS is unknown.



View larger version (55K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. NADPH oxidase inhibitors apocynin and DPI and an inhibitor of mitochondrial electron transfer chain complex I, rotenone, block high glucose-induced dichlofluorescein-sensitive ROS in mesangial cells (A) and high glucose-induced fibronectin secretion by tubular epithelial cells (B). (A) Synchronized quiescent mesangial cells grown on cover glass were incubated with 5.6 (control glucose [CG]) or 30 mM glucose (high glucose [HG]) for 1 hr in the presence or absence of apocynin (100 µM), DPI (100 nM), and rotenone (10 nM), washed with Dulbecco’s PBS and incubated in the dark for 20 min containing 5 mM 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate. Culture dishes were transferred to Leica DM IRB/E inverted microscope, equipped with 20x Fluotar objective and Leica TCS NT confocal attachment and the ROS generation was visualized. (B) Synchronized quiescent LLC-PK1 cells were incubated with CG or HG for 48 h in the presence or absence of apocynin (100 µM), DPI (100 nM), and rotenone (10 nM). Fibronectin secreted into the media was measured by Western blot analysis after electrophoresis under reducing condition. *P < 0.05 versus control glucose without inhibitor; +P < 0.05 versus high glucose without inhibitor.

 
High glucose also induces intracellular ROS indirectly through AGE and cytokines, including TGF-{beta}1 and Ang II. AGE increase intracellular ROS in neonatal mesangial (19) and proximal tubular epithelial cells (20). In human umbilical vein endothelial cells, AGE/receptor for AGE-mediated generation of ROS is NADPH oxidase dependent (21). AGE-induced activation of nuclear factor-{kappa}B (NF-{kappa}B), PKC, and TGF-{beta}1 in mesangial cells is effectively inhibited by antioxidants (22). TGF-{beta}1 increases intracellular ROS in mesangial (Figure 2A) and tubular epithelial (9) cells. TGF-{beta}1 upregulates the expression of p22phox, p47phox, p67phox, and gp91phox in rat mesangial cells (Figure 2B) and p22phox mRNA in tubular epithelial cells (Figure 2C), suggesting that TGF-{beta}1-induced ROS may be NADPH oxidase dependent. Ang II also induces ROS in glomerular mesangial (23) and tubular epithelial (12) cells. Ang II-induced ROS in vascular smooth muscle cells were shown to be derived from NADPH oxidase (24). ROS induce AGE (18) and upregulate TGF-{beta}1 (4,8), both of which, in turn, induce ROS generation in mesangial cells, thus providing an amplification loop in high glucose signaling in diabetic kidney (Figure 3).



View larger version (37K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. TGF-{beta}1 induces dichlofluorescein-sensitive ROS in mesangial cells (A) and upregulates NADPH oxidase subunit expression in mesangial (B) and tubular epithelial cells (C). (A) Intracellular ROS were measured as described in Figure 1, after incubating synchronized quiescent mesangial cells with 2 ng TGF-{beta}1/ml in the presence or absence of NAC (5 mM), catalase (500 U/ml), and trolox (500 µM) for 5 min. (B) NADPH oxidase subunits were visualized with immunocytochemistry after incubating synchronized quiescent mesangial cells with 2 ng TGF-{beta}1/ml for 48 h. (C) p22phox mRNA expression in LLC-PK1 cells was measured by RT-PCR after incubating synchronized quiescent LLC-PK1 cells with 2 ng TGF-{beta}1/ml for up to 48 h. Forward and reverse primers specific for p22phox (forward, 5'-GTTTGTGTGCCTGCTGGAGT-3'; reverse, 5'-TGGGCGGCTGCTTGATGGT-3') or GAPDH (forward, 5'-CCACCCATGGCAAATTCCATGGCA-3'; reverse, 5'-TCTAGACGGCAGGTCAGGTCCACC-3') were used.

 


View larger version (28K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 3. ROS-regulated signaling in renal cells cultured under high glucose. Mitochondrial electron transfer chain and receptor-stimulated NADPH oxidases are important sources of intracellular ROS generation under high glucose condition. High glucose-induced ROS activate signal transduction cascade and transcription factors, leading to upregulation of genes and proteins involved in ECM remodeling in the kidney. HG, high glucose; MCP-1, monocyte chemoattractant protein-1; RAGE, receptors for advanced glycation end products; Sp1, specificity protein 1.

 
ROS Activate Signal Transduction Cascade
Studer et al. (10) showed that high glucose-induced PKC activation in mesangial cells is effectively blocked by antioxidants vitamin E, N-acetyl cysteine (NAC), and taurine, suggesting that ROS mediate high glucose-induced PKC activation. We (25) demonstrated that antioxidant taurine effectively inhibits membrane translocation of PKC{delta} and PKC{epsilon} in streptozotocin-induced diabetic rat glomeruli, suggesting that ROS activate PKC in diabetic kidney as well.

Dunlop et al. (26) demonstrated significant activation of p38 mitogen-activated protein kinase (MAPK) in streptozotocin-induced diabetic rat glomeruli, whereas, in control glomeruli, H2O2 activated p38 MAPK. Wilmer et al. (27) showed that high glucose-induced activation of P38 MAPK in mesangial cells is effectively blocked by NAC or DPI. These studies suggest ROS-dependent activation of p38 MAPK in mesangial cells cultured under high glucose and in diabetic kidney. We observed that antioxidant lithospermate B (28,29) significantly inhibits p42/p44 MAPK and P38 MAPK activation in streptozotocin-induced diabetic rat renal cortex.

Wang et al. (30) observed that high glucose activates Janus kinase/signal transducers and activators of transcription (JAK/STAT) in mesangial cells and that high glucose-induced TGF-{beta}1 and fibronectin secretion is effectively inhibited by inhibition of JAK2 and STAT1. Although ROS have been shown to regulate JAK/STAT in both fibroblasts and A-431 carcinoma cells (31), it is not known whether ROS regulate JAK/STAT in mesangial cells or in diabetic kidney. These observations suggest that ROS mediate high glucose-induced activation of PKC, MAPK, and possibly JAK/STAT in diabetic kidney.

ROS Activate Transcription Factors
NF-{kappa}B and activated protein-1 (AP-1) are ubiquitous transcription factors that are activated by ROS (32). We have demonstrated that high glucose and exogenous H2O2 activate NF-{kappa}B (3) and AP-1 (4) in mesangial cells. NF-{kappa}B activation is required to upregulate monocyte chemotactic protein-1 expression in mesangial cells cultured under high glucose (3). Given that inflammatory events initiated by monocyte infiltration are involved in the pathogenesis of diabetic glomerular (33) as well as tubular injury (34), ROS-mediated NF-{kappa}B activation may play an important role in the pathogenesis of diabetic nephropathy. AP-1 mediates high glucose-induced activation of human TGF-{beta}1 promoter in mesangial cells (35). Mutation in either one or both AP-1 binding sites or the addition of curcumin, an AP-1 inhibitor, abolishes high glucose-induced TGF-{beta}1 promoter activity (35). We observed that high glucose-induced fibronectin secretion by NF-{kappa}B dominant negative as well as control mesangial cells was effectively inhibited by curcumin (Figure 4). These observations suggest that ROS-induced AP-1 may play an important role in high glucose-induced TGF-{beta}1 and fibronectin expression in mesangial cells. Du et al. (36) showed that high glucose-induced mitochondrial superoxide generation induces activation of specificity protein 1 and plasminogen activator inhibitor-1 (PAI-1) expression in bovine aortic endothelial cells. The exact role of AP-1 and specificity protein 1 in high glucose-induced TGF-{beta}1, PAI-1, and fibronectin upregulation in mesangial cells and in diabetic kidney remains to be elucidated.



View larger version (13K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 4. Curcumin, an inhibitor of AP-1, inhibits high glucose-induced fibronectin secretion in mesangial cells. Synchronized quiescent rat mesangial cells transfected with control vector (A) or I{kappa}B{alpha}M (B), as characterized previously (3), were incubated with 5.6 (control glucose [CG]) or 30 mM glucose (high glucose [HG]) in the presence or absence of curcumin 20 mM for 48 h. Fibronectin secreted into the media was measured by Western blot analysis after electrophoresis under reducing condition. *P < 0.05 versus control glucose without curcumin; +P < 0.05 versus high glucose without curcumin.

 
ROS Upregulate ECM Expression
TGF-{beta}1 is the key regulator of ECM remodeling in the mesangium leading to mesangial expansion (37) and of tubular epithelial-mesenchymal transition (EMT) (38) leading to tubulointerstitial fibrosis. TGF-{beta}1 upregulates not only ECM mRNA and proteins but also PAI-1 mRNA and protein expression and downregulates genes encoding proteases (39). PAI-1 induced by TGF-{beta}1 in mesangial cells inhibits plasminogen activator, decreases plasmin, and decreases ECM degradation (39). The observations that exogenous H2O2 or H2O2 continuously generated by GO upregulates the expression of mRNA and proteins of TGF-{beta}1 (4,8), PAI-1 (40), and fibronectin (4,8) in mesangial cells and that antioxidants effectively inhibit TGF-{beta}1, PAI-1, and fibronectin upregulation in mesangial cells cultured under high glucose (8,10,11,28,40) and in diabetic kidneys (11,28,41,42) suggest that ROS mediate ECM accumulation in diabetic glomeruli. We (9) recently demonstrated that exogenous H2O2 and TGF-{beta}1 upregulate PAI-1 and fibronectin expression and induce EMT in tubular epithelial cells as characterized by decrease in E-cadherin and increase in {alpha}-smooth muscle actin expression. Antioxidants NAC and catalase effectively inhibit TGF-{beta}1-induced EMT (9). Both NADPH oxidase inhibitors apocynin and DPI and an inhibitor of mitochondrial metabolism, rotenone, block high glucose-induced fibronectin upregulation in tubular epithelial cells (Figure 1B), suggesting that ROS may also play an important role in tubulointerstitial fibrosis in diabetic kidney.


   Conclusion
Top
 Abstract
 Introduction
 Mechanisms of High Glucose...
 Conclusion
References
 
ROS are induced in glomerular mesangial and tubular epithelial cells by high glucose, AGE, and cytokines. PKC, NADPH oxidase, and mitochondrial metabolism all seem to play a role in ROS generation. ROS activate signal transduction cascade and transcription factors, leading to upregulation of genes and proteins involved in glomerular mesangial expansion and tubulointerstitial fibrosis. Future studies to elucidate various other target molecules activated by ROS in renal cells cultured under high glucose and in diabetic kidney will allow a better understanding of the final cellular responses to high glucose.


   Acknowledgments
 
The original works performed in the authors’ laboratory were supported by a grant from the Korea Science and Engineering Foundation (KOSEF R01-2001-00119). Dr. Yang was a Year 2002 APEC postdoctoral fellow supported by KOSEF.


   Footnotes
 
Current affiliation of Drs. Yang and Jiang is National Institute of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.


   References
Top
 Abstract
 Introduction
 Mechanisms of High Glucose...
 Conclusion
 References
 

  1. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986, 1993[Abstract/Free Full Text]
  2. United Kingdom Prospective Diabetes Study 33: Intensive blood glucose control with sulphonylurea or insulin compared with conventional treatment and the risk of complication in patients with type 2 diabetes. Lancet 352: 837–853, 1998[CrossRef][Medline]
  3. Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB: Role of high glucose-induced nuclear factor-{kappa}B activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol 13: 894–902, 2002[Abstract/Free Full Text]
  4. Ha H, Lee HB: Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int 58 [Suppl 77]: S19–S25, 2000
  5. Ziyadeh FN, Sharma K, Ericksen M, Wolf G: Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-{beta}. J Clin Invest 93: 536–542, 1994
  6. Oh JH, Ha H, Yu MR, Lee HB: Sequential effects of high glucose on mesangial cell transforming growth factor-{beta} and fibronectin synthesis. Kidney Int 54: 1872–1878, 1998[CrossRef][Medline]
  7. Ayo SH, Radnik RA, Garoni JA, Glass WF II, Kreisberg JI: High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am J Pathol 136: 1339–1348, 1990[Abstract]
  8. Iglesias-De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, Rodriguez-Puyol M, Ziyadeh FN, Rodriguez-Puyol D: Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int 59: 87–95, 2001[CrossRef][Medline]
  9. Yang Y, Ha H, Lee HB: Role of reactive oxygen species in TGF-{beta}1-induced epithelial-mesenchymal transition [Abstract]. Nephrol Dial Transplant 18 [suppl 4]: 300, 2003
  10. Studer RK, Craven PA, Derubertis FR: Antioxidant inhibition of protein kinase C-signaled increase in transforming growth factor-beta in mesangial cells. Metabolism 46: 918–925, 1997[CrossRef][Medline]
  11. Ha H, Lee SH, Kim KH: Effects of rebamipide in a model of experimental diabetes and on the synthesis of transforming growth factor-beta and fibronectin, and lipid peroxidation induced by high glucose in cultured mesangial cells. J Pharmacol Exp Ther 281: 1457–1462, 1997[Abstract]
  12. Ha H, Yang Y, Lee HB: Mechanisms of reactive oxygen species generation in LLC-PK1 cells cultured under high glucose [Abstract]. J Am Soc Nephrol 13: 531A, 2002
  13. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945, 2000[Abstract]
  14. Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J: Phosphorylation of p47phox sites by PKC{alpha} {beta}II, {delta}, and {zeta}: Effect on binding to p22phox and on NADPH oxidase activation. Biochemistry 41: 7743–7750, 2002[CrossRef][Medline]
  15. Frey RS, Rahman A, Kefer JC, Minshall RD, Malik AB: PKC{zeta} regulates TNF-{alpha}-induced activation of NADPH oxidase in endothelial cells. Circ Res 17: 1012–1019, 2002
  16. Griendling KK, Sorescu D, Ushio-Fukai M: NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res 86: 494–501, 2000[Abstract/Free Full Text]
  17. Li N-M, Shah AM: Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem 277: 19952–19960, 2002[Abstract/Free Full Text]
  18. Nishikawa T, Edelstein D Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Bee be D, Oates PJ, Hammes H-P, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three different pathways of hyperglycemic damage. Nature 404: 787–790, 2000[CrossRef][Medline]
  19. Scivittaro V, Ganz MB, Weiss MF: AGEs induce oxidative stress and activate protein kinase C-{beta}II in neonatal mesangial cells. Am J Physiol 278: F676–F683, 2000
  20. Yamagishi S-I, Inagaki Y, Okamoto T, Amano S, Koga K, Takeuchi M: Advanced glycation end products inhibit de novo protein synthesis and induce TGF-{beta} overexpression in proximal tubular cells. Kidney Int 63: 464–473, 2003[CrossRef][Medline]
  21. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL: Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol 280: E685–E694, 2001
  22. Lal MA, Brismar H, Eklof AC, Aperia A: Role of oxidative stress in advanced glycation end product-induced mesangial cell activation. Kidney Int 61: 2006–2014, 2002[CrossRef][Medline]
  23. Jaimes EA, Galceran JM, Raij L: Angiotensin II induces superoxide anion production by mesangial cells. Kidney Int 54: 775–784, 1998[CrossRef][Medline]
  24. Seshiah PN, Weber DS, Rocic P, Valppu L, Tanuyama Y, Griendling KK: Angiotensin II stimulation of NAD(P)H oxidase activity: Upstream mediators. Circ Res 91: 406–413, 2002[Abstract/Free Full Text]
  25. Ha H, Yu MR, Choi YJ, Lee HB: Activation of protein kinase C-{delta} and C-{epsilon} by oxidative stress in early diabetic rat kidney. Am J Kidney Dis 38 [Suppl 1]: S204–S207, 2001[Medline]
  26. Dunlop ME, Muggli EE: Small heat shock protein alteration provide a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress. Kidney Int 57: 464–475, 2000[Medline]
  27. Wilmer WA, Dixon CL, Herbert C: Chronic exposure of human mesangial cells to high glucose environment activates the p38 MAPK pathway. Kidney Int 60: 858–871, 2001[CrossRef][Medline]
  28. Lee GT, Ha H, Jung M, Li HR, Hong SW, Cha BS, Lee HC, Cho DH: Delayed treatment with lithospermate B attenuates experimental diabetic renal injury. J Am Soc Nephrol 14: 709–720, 2003[Abstract/Free Full Text]
  29. Ha H, Yu MR, Lee GT, Lee HC, Lee HB: Reversal of extracellular signal-regulated kinase activation by lithospermate B in experimental diabetes [Abstract]. J Am Soc Nephrol 12: 836A, 2001
  30. Wang X, Shaw S, Amiri F, Eaton DC, Marrero MB: Inhibition of the JAK/STAT signaling pathway prevents the high glucose-induced increase in TGF-{beta} and fibronectin synthesis in mesangial cells. Diabetes 51: 3505–3509, 2002[Abstract/Free Full Text]
  31. Simon AR, Rai U, Fanburg BL, Cochran BH: Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 275: C1640–C1652, 1998
  32. Thannickal VJ, Fanburg BL: Reactive oxygen species in cell signaling. Am J Physiol 279: L1005–L1028, 2000
  33. Utimura R, Fujihara CK, Mattar AL, Malheiros DMAC, de Lourdes Noronha I, Zatz R: Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney Int 63: 209–216, 2003[CrossRef][Medline]
  34. Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K, Shimizu M, Takeda SI, Takasawa K, Yoshimura M, Kida H, Kobayashi KI, Mukaida N, Naito T, Matsushima K, Yokoyama H: Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int 58: 1492–1499, 2000[CrossRef][Medline]
  35. Weigert C, Sauer U, Brodbeck K, Pfilffer A, Haering HU, Schleicher ED: AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-{beta}1 promoter in mesangial cells. J Am Soc Nephrol 11: 2007–2016, 2000[Abstract/Free Full Text]
  36. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M: Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97: 12222–12226, 2000[Abstract/Free Full Text]
  37. Ziyadeh FN, Hoffman BB, Iglesias-De La Cruz MC, Han DC, Hong SW, Isono M, Chen S, Mcwan T, Sharma K: Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti-transforming growth factor-{beta} antibody in db/db mice. Proc Natl Acad Sci U S A 97: 8015–8020, 2000[Abstract/Free Full Text]
  38. Oldfield MD, Bach LS, Forbes JM, Nikolic-Pateerson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME: Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 108: 1853–1863, 2001[CrossRef][Medline]
  39. Baricos WH, Cortez SL, Deboisblanc M, Xin S: Transforming growth factor-{beta} is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J Am Soc Nephrol 10: 790–795, 1999[Abstract/Free Full Text]
  40. Ha H, Seo J, Lee EA, Kim YS, Lee HB: Reactive oxygen species mediate upregulation of plasminogen activator inhibitor-1 secretion by mesangial cells cultured under high glucose [Abstract]. J Am Soc Nephrol 12: 836A, 2001
  41. Ha H, Yu MR, Kim KH: Melatonin and taurine reduce early glomerulopathy in diabetic rats. Free Radic Biol Med 26: 944–950, 1999[CrossRef][Medline]
  42. Craven PA, Melhelim MF, Phillips SL, DeRubertis FR: Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. Diabetes 50: 2114–2125, 2001[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 DiabetesHome page
S. Simone, Y. Gorin, C. Velagapudi, H. E. Abboud, and S. L. Habib
Mechanism of Oxidative DNA Damage in Diabetes: Tuberin Inactivation and Downregulation of DNA Repair Enzyme 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine-DNA Glycosylase
Diabetes, October 1, 2008; 57(10): 2626 - 2636.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
J. Karalliedde, A. Smith, L. DeAngelis, V. Mirenda, A. Kandra, J. Botha, P. Ferber, and G. Viberti
Valsartan Improves Arterial Stiffness in Type 2 Diabetes Independently of Blood Pressure Lowering
Hypertension, June 1, 2008; 51(6): 1617 - 1623.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. Ohtomo, M. Nangaku, Y. Izuhara, S. Takizawa, C. v. Y. d. Strihou, and T. Miyata
Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model
Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1166 - 1172.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
Y. S. Kanwar, J. Wada, L. Sun, P. Xie, E. I. Wallner, S. Chen, S. Chugh, and F. R. Danesh
Diabetic Nephropathy: Mechanisms of Renal Disease Progression
Experimental Biology and Medicine, January 1, 2008; 233(1): 4 - 11.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
S. Prabhakar, J. Starnes, S. Shi, B. Lonis, and R. Tran
Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production
J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2945 - 2952.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. Djamali
Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts
Am J Physiol Renal Physiol, August 1, 2007; 293(2): F445 - F455.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
B. You, A. Ren, G. Yan, and J. Sun
Activation of Sphingosine Kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia
Diabetes, May 1, 2007; 56(5): 1445 - 1453.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. Djamali, E. A. Sadowski, R. J. Muehrer, S. Reese, C. Smavatkul, A. Vidyasagar, S. B. Fain, R. C. Lipscomb, D. H. Hullett, M. Samaniego-Picota, et al.
BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction
Am J Physiol Renal Physiol, February 1, 2007; 292(2): F513 - F522.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
K. Bedard and K.-H. Krause
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Physiol Rev, January 1, 2007; 87(1): 245 - 313.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
I. F. Benter, M. H. M. Yousif, C. Cojocel, M. Al-Maghrebi, and D. I. Diz
Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction
Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H666 - H672.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
S. V. Shah, R. Baliga, M. Rajapurkar, and V. A. Fonseca
Oxidants in Chronic Kidney Disease
J. Am. Soc. Nephrol., January 1, 2007; 18(1): 16 - 28.
[Abstract] [Full Text] [PDF]

Home page
 CJASNHome page
J. Uribarri and K. R. Tuttle
Advanced Glycation End Products and Nephrotoxicity of High-Protein Diets
Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1293 - 1299.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C.-H. Hsieh, K.-H. Liang, Y.-J. Hung, L.-C. Huang, D. Pei, Y.-T. Liao, S.-W. Kuo, M. S.-J. Bey, J.-L. Chen, and E. Y. Chen
Analysis of epistasis for diabetic nephropathy among type 2 diabetic patients
Hum. Mol. Genet., September 15, 2006; 15(18): 2701 - 2708.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
T. Samikkannu, J. J. Thomas, G. J. Bhat, V. Wittman, and T. J. Thekkumkara
Acute effect of high glucose on long-term cell growth: a role for transient glucose increase in proximal tubule cell injury
Am J Physiol Renal Physiol, July 1, 2006; 291(1): F162 - F175.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. Yung, C. Y. Y. Lee, Q. Zhang, S. K. Lau, R. C. W. Tsang, and T. M. Chan
Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-{beta}1 dependent and TGF-{beta}1 independent pathways
Nephrol. Dial. Transplant., June 1, 2006; 21(6): 1504 - 1513.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
N.-H. Kim, H. Rincon-Choles, B. Bhandari, G. G. Choudhury, H. E. Abboud, and Y. Gorin
Redox dependence of glomerular epithelial cell hypertrophy in response to glucose
Am J Physiol Renal Physiol, March 1, 2006; 290(3): F741 - F751.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
J. Asbun and F. J. Villarreal
The Pathogenesis of Myocardial Fibrosis in the Setting of Diabetic Cardiomyopathy
J. Am. Coll. Cardiol., February 21, 2006; 47(4): 693 - 700.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
L. Xia, H. Wang, H. J. Goldberg, S. Munk, I. G. Fantus, and C. I. Whiteside
Mesangial cell NADPH oxidase upregulation in high glucose is protein kinase C dependent and required for collagen IV expression
Am J Physiol Renal Physiol, February 1, 2006; 290(2): F345 - F356.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. Nanez, N. F. Alejandro, M. H. Falahatpisheh, J. K. Kerzee, J. B. Roths, and K. S. Ramos
Disruption of glomerular cell-cell and cell-matrix interactions in hydrocarbon nephropathy
Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1291 - F1303.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
J. B. de Haan, N. Stefanovic, D. Nikolic-Paterson, L. L. Scurr, K. D. Croft, T. A. Mori, P. Hertzog, I. Kola, R. C. Atkins, and G. H. Tesch
Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy
Am J Physiol Renal Physiol, September 1, 2005; 289(3): F544 - F551.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
Y. Rikitake and J. K. Liao
Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells
Circulation, June 21, 2005; 111(24): 3261 - 3268.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
F. Lang
Regulating Renal Drug Elimination?
J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1535 - 1536.
[Full Text] [PDF]

Home page
 HypertensionHome page
T. Mori and A. W. Cowley Jr.
Renal Oxidative Stress in Medullary Thick Ascending Limbs Produced by Elevated NaCl and Glucose
Hypertension, February 1, 2004; 43(2): 341 - 346.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, H. B.
Right arrow Articles by Ha, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, H. B.
Right arrow Articles by Ha, H.

HOME CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP