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Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Enhanced expression of two discrete isoforms of matrix metalloproteinase-2 in experimental and human diabetic
Sang Soo Kim1, Nari Shin2, Sun Sik Bae3
1Biomedical Research Institute and Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea.
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-κB 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.
Insights
Diabetes mellitus significantly increases matrix metalloproteinase-2 (MMP-2) isoforms, including the novel intracellular N-Terminal Truncated MMP-2 (NTT-MMP-2). Targeting these MMP-2 isoforms may offer new treatments for diabetic kidney disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Nephrology
Background:
- Matrix metalloproteinase-2 (MMP-2) has two isoforms: full-length secreted (FL-MMP-2) and intracellular N-Terminal Truncated (NTT-MMP-2).
- NTT-MMP-2 is generated via oxidative stress and alternate promoter activation in the MMP-2 first intron.
- Previous work indicated elevated MMP-2 isoforms in delayed graft function after renal transplantation.
Purpose of the Study:
- To investigate the impact of hyperglycemia and diabetes mellitus on MMP-2 isoform expression.
- To evaluate the in vitro and in vivo expression patterns of FL-MMP-2 and NTT-MMP-2 under diabetic conditions.
Main Methods:
- Quantified FL-MMP-2 and NTT-MMP-2 transcripts using qPCR in HK2 cells exposed to high glucose or 4-hydroxy-2-hexenal (HHE).
- Assessed the effect of NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) on isoform expression.
- Utilized the streptozotocin (STZ)-induced Type I diabetes mellitus murine model and human diabetic nephropathy renal biopsies.
Main Results:
- High glucose and HHE upregulated both MMP-2 isoforms in HK2 cells.
- PDTC inhibited high glucose-induced NTT-MMP-2 but not FL-MMP-2 expression.
- STZ-induced diabetes increased renal cortical FL-MMP-2 (1.8-fold) and NTT-MMP-2 ( >7-fold) expression.
- Human diabetic nephropathy biopsies showed significantly elevated FL-MMP-2 (12-fold) and NTT-MMP-2 (3-fold) expression.
Conclusions:
- Both FL-MMP-2 and NTT-MMP-2 isoforms are upregulated in experimental and human diabetic nephropathy.
- Selective inhibition of MMP-2 isoforms presents a potential therapeutic strategy for diabetic renal disease.
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