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Published on: July 15, 2015
Targeting Kidney Inflammation After Brain Death and Cold Storage: Investigating the Potential of an NLRP3
Naiane do Nascimento Gonçalves1, Heloisa Cristina Caldas1,2, Ludimila Leite Marzochi1
1Department of Medicine I, Laboratory of Immunology and Experimental Transplantation (LITEX), Medical School of São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.
Background:
Brain death (BD) and cold storage (CS) are critical factors that induce inflammation in donor kidneys, compromising organ quality. We investigated whether treating kidneys from BD rats with an inflammasome Nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor (MCC950) followed by CS could reduce kidney inflammation.
Methods:
BD rats were assigned to MCC950-treated or nontreated (NT) groups. Kidneys were evaluated immediately before CS (T0) and after 12 h (T12) and 24 h (T24) of CS. Mean arterial pressure, serum creatinine, gene/protein expression, and histology were evaluated.
Results:
At T0, MCC950 treatment did not affect mean arterial pressure but tended to reduce serum creatinine and ameliorated the histological score of acute tubular necrosis. However, MCC950 reduced NLRP3 , caspase-1 , interleukin (IL)-1β , IL-6 , Kim-1 , nuclear factor kappa B , tumor necrosis factor alpha , and caspase-3 gene expression while increasing IL-10 cytokine gene expression. After 12 h of CS, only the expression of the NLRP3 and caspase-1 genes decreased, and after 24 h of CS, no further changes in the gene expression profile were observed. The levels of the inflammasome proteins NLRP3, caspase-1, and IL-1β consistently decreased across all time points (T0, T12, and T24).
Conclusions:
These findings suggest that MCC950 treatment holds promise for mitigating the proinflammatory state observed in kidneys after BD and CS.
Insights
Treating brain-dead (BD) rat kidneys with MCC950, an inflammasome inhibitor, reduced inflammation and improved organ quality before and during cold storage (CS). MCC950 shows promise for preserving donor kidneys.
Area of Science:
- Organ transplantation
- Inflammation research
- Renal pathology
Background:
- Brain death (BD) and cold storage (CS) induce inflammation in donor kidneys, negatively impacting organ quality.
- The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in this inflammatory process.
Purpose of the Study:
- To investigate the efficacy of MCC950, an NLRP3 inflammasome inhibitor, in mitigating kidney inflammation caused by BD and CS.
- To assess the impact of MCC950 treatment on kidney injury markers and inflammatory gene/protein expression.
Main Methods:
- Kidneys from BD rats were treated with MCC950 or a non-treated (NT) control.
- Kidneys were evaluated at baseline (T0) and after 12 (T12) and 24 (T24) hours of CS.
- Assessments included mean arterial pressure, serum creatinine, histology, and gene/protein expression of inflammatory markers.
Main Results:
- MCC950 treatment tended to reduce serum creatinine and improve histological scores for acute tubular necrosis at T0.
- MCC950 significantly reduced the gene expression of NLRP3, caspase-1, IL-1β, IL-6, Kim-1, NF-κB, TNF-α, and caspase-3, while increasing IL-10.
- Protein levels of NLRP3, caspase-1, and IL-1β were consistently decreased by MCC950 across all time points.
Conclusions:
- MCC950 treatment effectively mitigates the proinflammatory state in kidneys subjected to BD and CS.
- This suggests MCC950 is a potential therapeutic strategy for improving donor kidney quality and transplantation outcomes.
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