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Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats
Jens Lutz1, Yousheng Yao, Erwei Song
1Department of Nephrology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Background:
Chronic allograft nephropathy (CAN) belongs to the major causes of long-term kidney allograft failure. One of the histologic hallmarks of CAN is interstitial fibrosis, influenced by matrix metalloproteinases (MMPs) that are controlling extracellular matrix (ECM) degradation. Whether MMPs affect the development and progression of CAN is not clear so far. To analyze the role of MMPs in CAN, we investigated the effects of an early and a late application of BAY 12-9566, an inhibitor of MMP-2, -3, and -9 on the development and progression of CAN in a rat kidney-transplantation model.
Methods:
Fisher kidneys were orthotopically transplanted into Lewis recipients that were treated with BAY 12-9566 (15 mg/kg per day) or vehicle either for the first 10 days after transplantation (early treatment) or from week 12 to week 20 after transplantation (late treatment). Proteinuria was analyzed every 4 weeks up to week 20 after transplantation when kidney grafts were removed for further analysis.
Results:
Early MMP-inhibition resulted in a significantly reduced 24-hour protein excretion that was paralleled by a lower grade of CAN after 20 weeks. However, late MMP inhibition starting at week 12 after transplantation resulted in significantly higher proteinuria and a higher grade of CAN as compared with controls. Furthermore, transforming growth factor-beta and platelet-derived growth factor-B chain mRNA levels were significantly increased in these animals.
Conclusions:
Inhibition of MMPs early after transplantation reduced the development and progression of CAN but promoted CAN if initiated at later stages. Thus, MMPs are involved in the development and progression of CAN.
Insights
Early inhibition of matrix metalloproteinases (MMPs) reduced chronic allograft nephropathy (CAN) development. However, late MMP inhibition worsened CAN, indicating MMPs
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic allograft nephropathy (CAN) is a primary cause of long-term kidney transplant failure.
- Interstitial fibrosis, a hallmark of CAN, is influenced by matrix metalloproteinases (MMPs) regulating extracellular matrix (ECM) degradation.
- The precise role of MMPs in CAN development and progression remains unclear.
Purpose of the Study:
- To investigate the role of MMPs in the development and progression of CAN.
- To evaluate the effects of early versus late administration of an MMP inhibitor (BAY 12-9566) on CAN in a rat kidney transplant model.
Main Methods:
- Fisher kidneys were transplanted into Lewis rats.
- Rats received either BAY 12-9566 (MMP inhibitor) or vehicle.
- Treatment was administered either early (first 10 days post-transplant) or late (weeks 12-20 post-transplant).
- Proteinuria was monitored, and kidney grafts were analyzed at 20 weeks.
Main Results:
- Early MMP inhibition significantly reduced proteinuria and the severity of CAN.
- Late MMP inhibition led to significantly increased proteinuria and a higher grade of CAN compared to controls.
- Late MMP inhibition also resulted in increased mRNA levels of transforming growth factor-beta and platelet-derived growth factor-B chain.
Conclusions:
- Matrix metalloproteinases play a dual role in chronic allograft nephropathy.
- Early inhibition of MMPs ameliorates CAN development and progression.
- Late inhibition of MMPs exacerbates CAN, suggesting a critical time-dependent involvement of MMPs.