Enhanced expression of two discrete isoforms of matrix metalloproteinase-2 in experimental and human diabetic nephropathy

被引：29

作者：

Kim, Sang Soo ^{[1
,2
]}

Shin, Nari ^{[3
]}

Bae, Sun Sik ^{[4
,5
]}

Lee, Min Young ^{[1
,2
]}

Rhee, Harin ^{[1
,2
]}

Kim, Il Young ^{[6
,7
]}

Seong, Eun Young ^{[1
,2
]}

Lee, Dong Won ^{[6
,7
]}

Lee, Soo Bong ^{[6
,7
]}

Kwak, Ihm Soo ^{[1
,2
]}

Lovett, David H. ^{[8
]}

Song, Sang Heon ^{[1
,2
]}

机构：

[1] Pusan Natl Univ Hosp, Biomed Res Inst, Busan, South Korea

[2] Pusan Natl Univ Hosp, Dept Internal Med, Busan, South Korea

[3] Pusan Natl Univ, Dept Pathol, Yangsan Hosp, Yangsan, Gyeongnam, South Korea

[4] Pusan Natl Univ, Sch Med, MRC Ischem Tissue Regenerat, Med Res Inst, Yangsan, South Korea

[5] Pusan Natl Univ, Sch Med, Dept Phamacol, Yangsan, South Korea

[6] Pusan Natl Univ, Yangsan Hosp, Res Inst Convergence Biomed Sci & Technol, Yangsan, Gyeongnam, South Korea

[7] Pusan Natl Univ, Yangsan Hosp, Dept Internal Med, Yangsan, Gyeongnam, South Korea

[8] Univ Calif San Francisco, San Francisco Dept Vet Affairs Med Ctr, Dept Med, San Francisco, CA 94143 USA

来源：

PLOS ONE | 2017年 / 12卷 / 02期

关键词：

OXIDATIVE STRESS; INHIBITION; INJURY;

D O I：

10.1371/journal.pone.0171625

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background We recently reported on the enhanced expression of two isoforms of matrix metalloproteinase-2 (MMP-2) in human renal transplantation delayed graft function. These consist of the conventional secreted, full length MMP-2 isoform (FL-MMP-2) and a novel intracellular N Terminal Truncated isoform (NTT-MMP-2) generated by oxidative stress-mediated activation of an alternate promoter in the MMP-2 first intron. Here we evaluated the effect of hyperglycemia and diabetes mellitus on the in vitro and in vivo expression of the two MMP-2 isoforms. Methods We quantified the abundance of the FL-MMP-2 and NTT-MMP-2 transcripts by qPCR in HK2 cells cultured in high glucose or 4-hydroxy-2-hexenal (HHE) and tested the effects of the NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC). The streptozotocin (STZ) murine model of Type I diabetes mellitus and renal biopsies of human diabetic nephropathy were used in this study. Results Both isoforms of MMP-2 in HK2 cells were upregulated by culture in high glucose or with HHE. PDTC treatment did not suppress high glucose -mediated FL-MMP-2 expression but potently inhibited NTT-MMP-2 expression. With STZ-treated mice, renal cortical expression of both isoforms was increased (FL-MMP-2, 1.8-fold; NTT-MMP-2, greater than 7-fold). Isoform-specific immunohistochemical staining revealed low, but detectable levels of the FL-MMP-2 isoform in controls, while NTT-MMP-2 was not detected. While there was a modest increase in tubular epithelial cell staining for FL-MMP-2 in STZ-treated mice, NTT-MMP-2 was intensely expressed in a basolateral pattern. FL-MMP-2 and NTT-MMP-2 isoform expression as quantified by qPCR were both significantly elevated in renal biopsies of human diabetic nephropathy (12 -fold and 3 -fold, respectively). Conclusions The expression of both isoforms of MMP-2 was enhanced in an experimental model of diabetic nephropathy and in human diabetic nephropathy. Selective MMP-2 isoform inhibition could offer a novel approach for the treatment of diabetic renal disease.

引用

页数：14

共 19 条

[1] Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB and JunB [J].