Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity

Luo,Pengli; Peng,Hui; Li,Canming; Ye,Zengchun; Tang,Hua; Tang,Ying; Chen,Cailian; Lou,Tanqi

doi:10.3892/mmr.2015.3269

Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity

Authors:
- Pengli Luo
- Hui Peng
- Canming Li
- Zengchun Ye
- Hua Tang
- Ying Tang
- Cailian Chen
- Tanqi Lou
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Affiliations: Department of Nephrology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China, Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China, Department of Nephrology, The Second Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510000, P.R. China
Published online on: January 29, 2015 https://doi.org/10.3892/mmr.2015.3269
Pages: 4447-4453

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Abstract

The present study aimed to investigate the effects of advanced glycation end‑products (AGEs) on the permeability of glomerular endothelial cells (GEnCs) and determine whether enhanced permeability was due to degradation of tight junction (TJ) complexes by matrix metalloproteinases (MMPs). Cultured monolayers of GEnCs were exposed to AGEs at different doses and treatment durations in the presence or absence of the organic MMP‑2/9 inhibitor (2R)‑2‑((4‑biphenyl sulfony‑l)amino)‑3‑phenylproprionic acid) (BiPs). Expression of the TJ proteins occludin and claudin‑5 was determined by western blot analysis and immunofluorescence, while the permeability of the GEnCs was measured using transendothelial electrical resistance and by diffusion of 4 kDa fluorescein isothiocyanate (FITC)‑dextran. The activities of MMP‑2 and MMP‑9 were assayed using gelatin zymography. The results indicated that AGE‑treated cultures significantly reduced occludin and claudin‑5 immunoreactivity. Similarly, the surface expression of these proteins was significantly reduced and rows of TJs which normally connect endothelial cells became discontinuous or fractured following AGE exposure. Disruption of TJs was accompanied by significantly reduced transendothelial resistance and hyperpermeability to FITC‑dextran. Treatment with AGEs evoked a dose‑ and time‑dependent upregulation of MMP‑2 and MMP‑9. However, co‑administration of AGEs and BiPS, an inhibitor of MMP‑2/MMP‑9, inhibited the downregulation of occludin and claudin‑5, with a concomitant reversal of GEnC monolayer hyperpermeability. In conclusion, AGEs promoted glomerular hyperpermeability in vitro by the MMP‑mediated disruption of TJs. Chronic elevation of endothelial cell AGEs in diabetes mellitus may contribute to glomerular hyperpermeability by inducing the overexpression of MMPs, which degrade TJs, leading to proteinuria.

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1	Bhonsle HS, Korwar AM, Chougale AD, Kote SS, Dhande NL, Shelgikar KM and Kulkarni MJ: Proteomic study reveals down-regulation of apolipoprotein A1 in plasma of poorly controlled diabetes: a pilot study. Mol Med Rep. 7:495–498. 2013.
2	Tooke JE: Microvasculature in diabetes. Cardiovasc Res. 32:764–771. 1996. View Article : Google Scholar : PubMed/NCBI
3	Bonnardel-Phu E, Wautier JL, Schmidt AM, Avila C and Vicaut E: Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo. Diabetes. 48:2052–2058. 1999. View Article : Google Scholar : PubMed/NCBI
4	Svensjo E, Arfors KE, Raymond RM and Grega GJ: Morphological and physiological correlation of bradykinin-induced macromolecular efflux. Am J Physiol. 236:H600–H606. 1979.PubMed/NCBI
5	Bi YL, Wu MF, Lu LX, Du F, Sun XT, Tang SF and Xu GT: Functions of corneal endothelial cells do not change after uptake of superparamagnetic iron oxide nanoparticles. Mol Med Rep. 7:1767–1772. 2013.PubMed/NCBI
6	Leto G, Pricci F, Amadio L, Iacobini C, Cordone S and Diaz-Horta O: Increased retinal endothelial cell monolayer permeability induced by the diabetic milieu: Role of advanced non-enzymatic glycation and polyol pathway activation. Diabetes Metab Res Rev. 17:448–458. 2001. View Article : Google Scholar
7	Bonnardel-Phu E, Wautier JL and Vicaut E: Advanced glycation end products are involved in microvascular permeability changes observed in microcirculation of diabetic rats in vivo. J Mal Vasc. 25:122–127. 2000.PubMed/NCBI
8	Soulis-Liparota T, Cooper ME, Dunlop M and Jerums G: The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the sprague-dawley rat. Diabetologia. 38:387–394. 1995. View Article : Google Scholar : PubMed/NCBI
9	Rojas A and Morales MA: Advanced glycation and endothelial functions: A link towards vascular complications in diabetes. Life Sci. 76:715–730. 2004. View Article : Google Scholar : PubMed/NCBI
10	Camici M: Renal glomerular permselectivity and vascular endothelium. Biomed Pharmacother. 59:30–47. 2005. View Article : Google Scholar : PubMed/NCBI
11	Beisswenger PJ, Makita Z, Curphey TJ, Moore LL and Jean S and Jean S: Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes. Diabetes. 44:824–829. 1995. View Article : Google Scholar : PubMed/NCBI
12	Thrailkill KM, Clay Bunn R and Fowlkes JL: Matrix metalloproteinases: Their potential role in the pathogenesis of diabetic nephropathy. Endocrine. 35:1–10. 2009. View Article : Google Scholar :
13	Giebel SJ, Menicucci G, McGuire PG and Das A: Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest. 85:597–607. 2005. View Article : Google Scholar : PubMed/NCBI
14	Death AK, Fisher EJ, McGrath KC and Yue DK: High glucose alters matrix metalloproteinase expression in two key vascular cells: Potential impact on atherosclerosis in diabetes. Atherosclerosis. 168:263–269. 2003. View Article : Google Scholar : PubMed/NCBI
15	Thrailkill KM, Bunn RC, Moreau CS, Cockrell GE, Simpson PM and Coleman HN: Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care. 30:2321–2326. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wang L, Wu J, Zhang W, Zhi Y, Wu Y, Jiang R and Yang R: Effects of aspirin on the ERK and PI3K/Akt signaling pathways in rats with acute pulmonary embolism. Mol Med Rep. 8:1465–1471. 2013.PubMed/NCBI
17	Ahuja TS, Gopalani A, Davies P and Ahuja H: Matrix metalloproteinase-9 expression in renal biopsies of patients with hiv-associated nephropathy. Nephron Clin Pract. 95:c100–c104. 2003. View Article : Google Scholar : PubMed/NCBI
18	Jung JY, Oh JH, Kim YK, Shin MH, Lee D and Chung JH: Acute UV irradiation increases heparin sulfate proteoglycan levels in human skin. J Korean Med Sci. 27:300–306. 2012. View Article : Google Scholar : PubMed/NCBI
19	Lauhio A, Sorsa T, Srinivas R, Stenman M, Tervahartiala T and Stenman UH: Urinary matrix metalloproteinase -8, -9, -14 and their regulators (try-1, try-2, tati) in patients with diabetic nephropathy. Ann Med. 40:312–320. 2008. View Article : Google Scholar : PubMed/NCBI
20	Peng H, Wang C, Ye ZC, Chen YR, Zhang J, Chen ZJ, Yu XQ and Lou TQ: How increased vegf induces glomerular hyperpermeability: A potential signaling pathway of rac1 activation. Acta Diabetol. 47:57–63. 2009. View Article : Google Scholar : PubMed/NCBI
21	Huang W, Eum SY, András IE, Hennig B and Toborek M: PPARalpha and PPARgamma attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities. FASEB J. 23:1596–1606. 2009. View Article : Google Scholar : PubMed/NCBI
22	Yang Y, Estrada EY, Thompson JF, Liu W and Rosenberg GA: Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 27:697–709. 2007.
23	Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY and Lipton SA: A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci. 25:6401–6408. 2005. View Article : Google Scholar : PubMed/NCBI
24	Bojarski C, Weiske J, Schoneberg T, Schroder W, Mankertz J, Schulzke J, Florian P, Fromm M, Tauber R and Huber O: The specific fates of tight junction proteins in apoptotic epithelial cells. J Cell Sci. 117:2097–2107. 2004. View Article : Google Scholar : PubMed/NCBI
25	Sun X, Han F, Yi J, Hou N and Cao Z: The effect of telomerase activity on vascular smooth muscle cell proliferation in type 2 diabetes in vivo and in vitro. Mol Med Rep. 7:1636–1640. 2013.PubMed/NCBI
26	Liu W, Hendren J, Qin XJ, Shen J and Liu KJ: Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem. 108:811–820. 2009. View Article : Google Scholar : PubMed/NCBI
27	Gonzalez-Mariscal L, Tapia R and Chamorro D: Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta. 1778:729–756. 2008. View Article : Google Scholar
28	Anderson JM and Van Itallie CM: Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. 1:a0025842009. View Article : Google Scholar :
29	Schneeberger EE and Lynch RD: The tight junction: A multifunctional complex. Am J Physiol Cell Physiol. 286:C1213–C1228. 2004. View Article : Google Scholar : PubMed/NCBI
30	Feldman GJ, Mullin JM and Ryan MP: Occludin: Structure, function and regulation. Adv Drug Deliv Rev. 57:883–917. 2005. View Article : Google Scholar : PubMed/NCBI
31	Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y and Tsukita S: Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol. 13:875–886. 2002.PubMed/NCBI
32	Paris L, Tonutti L, Vannini C and Bazzoni G: Structural organization of the tight junctions. Biochim Biophys Acta. 1778:646–659. 2008. View Article : Google Scholar
33	Harhaj NS and Antonetti DA: Regulation of tight junctions and loss of barrier function in pathophysiology. Int J Biochem Cell Biol. 36:1206–1237. 2004. View Article : Google Scholar : PubMed/NCBI
34	Xu ZC, Zhang Q and Li H: Differentiation of human hair follicle stem cells into endothelial cells induced by vascular endothelial and basic fibroblast growth factors. Mol Med Rep. 9:204–210. 2014.