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Abstract: SA-PO105

Inflammatory Pathway in Crystalline Nephropathy: Modulation by Uromodulin and Its Potential Renoprotective Role

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • de Araujo, Larissa, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
  • El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Oliveira-Souza, Maria, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Sao Paulo, São Paulo, Brazil
Background

Uromodulin (UMOD) plays a crucial immunomodulatory role in the kidney. We hypothesize that this function is impaired in acute kidney injury (AKI) caused by crystalline nephropathy and that exogenous administration of UMOD may offer a renoprotective effect in this condition.

Methods

8-week-old C57BL/6J mice were randomly allocated into four groups: 1. Control (saline 0.9%,i.p); 2. UMOD (exogenous UMOD–5μg/animal, single injection i.p); 3. NaOx (sodium oxalate–9mg/100g of body weight, single injection i.p); 4. NaOx administration and UMOD treatment. The animals were placed in metabolic cages for 24 hours before euthanasia and organ harvest. The results presented as mean ± S.D. were analyzed by two-way ANOVA and a Bonferroni post hoc test using GraphPad Prism software. p<0.05 was considered statistically significant.

Results

Crystal-positive medullary and cortical areas were increased in NaOx group. Co-treatment with exogenous UMOD prevented medullary crystal formation [NaOx+UMOD:1.3±0.8vsNaOx:5.0±1.6,p=<0.0001.Interaction p=<0.0001], but not cortical. Protein-positive medullary and cortical areas were increased in NaOx group.The co-treatment with exogenous UMOD prevented these changes [Medullary=NaOx+UMOD:2.0±2.2 vs NaOx:17.1±17.5,p=0.0250.Interaction p=0.0554/Cortical =NaOx+UMOD:0.8±0.4 vs NaOx:2.7±2.2,p=0.0397.Interaction p=0.0717].Treatment with NaOx significantly increased mRNA expression for KIM-1, NGAL, Ki67, MCP-1, TNFα, IL-1β, IL-6, CXCL1, and CXCL10,consistent with kidney injury.The mRNA expression for CCL19 significantly decreased in NaOx group.Co-treatment with exogenous UMOD prevented these changes (Fold change from control for NaOx+UMOD vs. NaOx, respectively):KIM-1 [95.2±121.7 vs. 730.0±182.5,p=<0.0001.Interaction p=0.0001],NGAL [2.5±2.1 vs. 86.4±19.3,p=<0.0001.Interaction p=0.0001],Ki67[2.0±1.0 vs. 5.7±1.7,p=0.0001.Interaction p=0.0006],MCP-1[1.9±1.8 vs. 8.2±3.8,p=0.0008.Interaction p=0.0030],TNFα[1.3±0.7 vs. 4.0±2.2, p=0.0087.Interaction p=0.0216],IL-6[5.4±7.5 vs. 84.4±46.2,p=0.0002. Interaction p=0.0010], CXCL1[8.4±15.9 vs. 1.2±0.4,p=0.0001.Interaction p= 0.0003],CXCL10[1.0±0.5 vs. 6.5±3.2,p=0.0005.Interaction p= 0.0030],CCL19[1.0±0.4 vs.0.1±0.1,p= 0.0066.Interaction p=0.0014].

Conclusion

The exogenous UMOD may have a renoprotective effect on nephropathy crystalline-induced AKI by modulating kidney inflammation.

Funding

  • Government Support – Non-U.S.