Background: High blood glucose is characteristic of diabetic nephropathy (DN). Both lectin-like ox-LDL receptor-1 (LOX-1) and renal tubular epithelial cells apoptosis reportedly are important for the pathogenesis and progression of DN. In this study, we explored the regulatory effects of high glucose on the expression of LOX-1 and its impact on oxLDL-induced apoptosis in human renal proximal tubular epithelial cells (HRPTEpCs). Methods: Primary HRPTEpCs were treated with high glucose with or without concurrent treatment with selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 or lentiviral knockdown of LOX-1. HRPTEpCs cultured in normal glucose concentration (5.5 mmol/l) was used as a control. Results and Conclusion: High glucose concentration dependency increased the expression of LOX-1, which led to increased ox-LDL binding in HRPTEpCs. In addition, high glucose upregulated the LOX-1 gene promoter activity but not its mRNA stability in HRPTEpCs; the effect was abolished by PD169316. Furthermore, high glucose markedly enhanced oxLDL-induced apoptosis in HRPTEpCs, which was largely abolished by knockdown of LOX-1. This study demonstrates that high glucose induces the expression of LOX-1 at the gene promoter/transcription level mainly by a p38 MAPK-dependent mechanism, which enhances oxLDL-induced apoptosis in renal tubular epithelial cells. It adds new insights into the molecular mechanisms underlying DN.

Keywords:
High glucose, Diabetic nephropathy, Lectin-like ox-LDL receptor-1, Oxidized LDL, Renal proximal tubular epithelial cell, Apoptosis
1.
Yamamoto N, Toyoda M, Abe M, Kobayashi T, Kobayashi K, Kato M, Miyauchi M, Kimura M, Umezono T, Suzuki D: Lectin-like oxidized LDL receptor-1 (LOX-1) expression in the tubulointerstitial area likely plays an important role in human diabetic nephropathy. Intern Med 2009;48:189-194.
2.
Allen DA, Harwood S, Varagunam M, Raftery MJ, Yaqoob MM: High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases. FASEB J 2003;17:908-910.
3.
Zhang X, Zhao Y, Chu Q, Wang ZY, Li H, Chi ZH: Zinc modulates high glucose-induced apoptosis by suppressing oxidative stress in renal tubular epithelial cells. Biol Trace Elem Res 2014;158:259-267.
4.
Taye A, El-Sheikh AA: Lectin-like oxidized low-density lipoprotein receptor 1 pathways. Eur J Clin Invest 2013;43:740-745.
5.
Xu Y, Ruan S, Xie H, Lin J: Role of LOX-1 in Ang II-induced oxidative functional damage in renal tubular epithelial cells. Int J Mol Med 2010;26:679-690.
6.
Zhou MS, Schuman IH, Jaimes EA, Raij L: Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-beta, and fibronectin with concomitant increase in nitric oxide bioavailability. Am J Physiol Renal Physiol 2008;295:F53-F59.
7.
Kelly KJ, Wu P, Patterson CE, Temm C, Dominguez JH: LOX-1 and inflammation: a new mechanism for renal injury in obesity and diabetes. Am J Physiol Renal Physiol 2008;294:F1136-F1145.
8.
Kim HJ, Moradi H, Yuan J, Norris K, Vaziri ND: Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney. Am J Physiol Renal Physiol 2009;296:F1297-F1306.
9.
Nosadini R, Tonolo G: Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes. Nutr Metab Cardiovasc Dis 2011;21:79-85.
10.
Tonolo G, Cherchi S: Tubulointerstitial disease in diabetic nephropathy. Int J Nephrol Renovasc Dis 2014;7:107-115.
11.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001;25:402-408.
12.
Stephan ZF, Yurachek EC: Rapid fluorometric assay of LDL receptor activity by DiI-labeled LDL. J Lipid Res 1993;34:325-330.
13.
Chen M, Narumiya S, Masaki T, Sawamura T: Conserved C-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized low-density-lipoprotein binding. Biochem J 2001;355(pt 2):289-296.
14.
Doyle A, Griffiths JB and Newell DG: Cell and tissue culture: laboratory procedures. Chichester, John Wiley & Sons, Inc., 1995.
15.
Chen J, Liu Y, Liu H, Hermonat PL, Mehta JL: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis. Biochem J 2006;393(pt 1):255-265.
16.
Wang X, Wu H, Miller AH: Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry 2004;9:65-75.
17.
Mackness MI, Durrington PN: Lipoprotein separation and analysis for clinical studies; in Converse CA, Skinner ER (eds): Lipoprotein Analysis: a Practical Approach. Oxford, Oxford University Press, 1997, pp 1-42.
18.
Lu H, Yao K, Huang D, Sun A, Zou Y, Qian J, Ge J: High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells. Cardiovasc Diabetol 2013;12:80.
19.
Li L, Sawamura T, Renier G: Glucose enhances endothelial LOX-1 expression: role for LOX-1 in glucose-induced human monocyte adhesion to endothelium. Diabetes 2003;52:1843-1850.
20.
Rudijanto A: Calcium channel blocker (diltiazem) inhibits apoptosis of vascular smooth muscle cell exposed to high glucose concentration through lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) pathway. Acta Med Indones 2010;42:59-65.
21.
Zhang WF, Xu YY, Xu KP, Wu WH, Tan GS, Li YJ, Hu CP: Inhibitory effect of selaginellin on high glucose-induced apoptosis in differentiated PC12 cells: role of NADPH oxidase and LOX-1. Eur J Pharmacol 2012;694:60-68.
22.
Wu H, Shi Y, Deng X, Su Y, Du C, Wei J, Ren Y, Wu M, Hou Y, Duan H: Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice. Mol Cell Endocrinol 2015;417:27-35.
23.
Azeem E, Gillani SW, Siddiqui A, Mian RI, Poh V, Sulaiman SA, Baig MR: Oxidative stress correlates (OSC) in diabetes mellitus patients. Curr Diabetes Rev 2015, Epub ahead of print.
24.
Zhou G, Liu X, Cheung AK, Huang Y: Efficacy of aliskiren, compared with angiotensin II blockade, in slowing the progression of diabetic nephropathy in db/db mice: should the combination therapy be a focus? Am J Transl Res 2015;7:825-840.
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2016
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