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Two Distinct Isoforms of Matrix Metalloproteinase-2 Are Associated with Human Delayed Kidney Graft Function.

Wanga S, Ceron CS, Delgado C, Joshi SK, Spaulding K, Walker JP, Song S, Olson JL, Lovett DH - PLoS ONE (2015)

Bottom Line: These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes.Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response.We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC), in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

No MeSH data available.


Related in: MedlinePlus

Ranking of serial biopsy sections for degree of tubular injury and immunohistochemistry staining.Serial sections of protocol and DGF biopsies were stained for NTT-MMP-2 and FL-MMP-2 with hematoxylin/eosin and ranked according to injury score. Representative results for injury score 1. (A, B, C X 300; D, E, F X 600).
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pone.0136276.g004: Ranking of serial biopsy sections for degree of tubular injury and immunohistochemistry staining.Serial sections of protocol and DGF biopsies were stained for NTT-MMP-2 and FL-MMP-2 with hematoxylin/eosin and ranked according to injury score. Representative results for injury score 1. (A, B, C X 300; D, E, F X 600).

Mentions: Figs 3, 4, 5 and 6 are comprised of serial sections of DGF renal biopsies ranked according to immunohistochemical staining intensity and tubular injury score. Grading reflects analyses of the entire biopsy core. Note that the staining intensity for FL-MMP-2 is greater than NTT-MMP-2 for all levels of tubular injury. This is consistent with the results of qPCR detailed below, in which the transcript abundance of NTT-MMP-2 is considerably less than that of the FL-MMP-2 isoform. The serial sections demonstrate that staining for the FL-MMP-2 and NTT-MMP-2 isoforms occurs within the same tubular cellular segments. Most importantly, the serial sections demonstrate that the tubular segments with the most prominent FL and NTT-MMP-2 isoform expression align with the areas of tubular epithelial cell injury in the H/E-stained serial sections Thus, FL-MMP-2 and NTT-MMP-2 are co-expressed and tubular injury is linked to the location and intensity of expression of both MMP-2 isoforms.


Two Distinct Isoforms of Matrix Metalloproteinase-2 Are Associated with Human Delayed Kidney Graft Function.

Wanga S, Ceron CS, Delgado C, Joshi SK, Spaulding K, Walker JP, Song S, Olson JL, Lovett DH - PLoS ONE (2015)

Ranking of serial biopsy sections for degree of tubular injury and immunohistochemistry staining.Serial sections of protocol and DGF biopsies were stained for NTT-MMP-2 and FL-MMP-2 with hematoxylin/eosin and ranked according to injury score. Representative results for injury score 1. (A, B, C X 300; D, E, F X 600).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574928&req=5

pone.0136276.g004: Ranking of serial biopsy sections for degree of tubular injury and immunohistochemistry staining.Serial sections of protocol and DGF biopsies were stained for NTT-MMP-2 and FL-MMP-2 with hematoxylin/eosin and ranked according to injury score. Representative results for injury score 1. (A, B, C X 300; D, E, F X 600).
Mentions: Figs 3, 4, 5 and 6 are comprised of serial sections of DGF renal biopsies ranked according to immunohistochemical staining intensity and tubular injury score. Grading reflects analyses of the entire biopsy core. Note that the staining intensity for FL-MMP-2 is greater than NTT-MMP-2 for all levels of tubular injury. This is consistent with the results of qPCR detailed below, in which the transcript abundance of NTT-MMP-2 is considerably less than that of the FL-MMP-2 isoform. The serial sections demonstrate that staining for the FL-MMP-2 and NTT-MMP-2 isoforms occurs within the same tubular cellular segments. Most importantly, the serial sections demonstrate that the tubular segments with the most prominent FL and NTT-MMP-2 isoform expression align with the areas of tubular epithelial cell injury in the H/E-stained serial sections Thus, FL-MMP-2 and NTT-MMP-2 are co-expressed and tubular injury is linked to the location and intensity of expression of both MMP-2 isoforms.

Bottom Line: These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes.Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response.We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC), in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

No MeSH data available.


Related in: MedlinePlus