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Kidney Week

Abstract: SA-PO495

Transcriptional Inhibitory Peptides of NFκB and JAK/STAT Pathways Improve Renal Damage in BTBR ob/ob Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Opazo-Ríos, Lucas, Universidad Austral de Chile, Valdivia, Valdivia, Chile
  • Plaza, Anita, Universidad Austral de Chile, Valdivia, Valdivia, Chile
  • Sanchez, Yenniffer, Universidad Austral de Chile, Valdivia, Valdivia, Chile
  • Carpio, Daniel, Universidad Austral de Chile, Valdivia, Valdivia, Chile
  • Droguett, Maria Alejandra, Universidad Austral de Chile, Valdivia, Valdivia, Chile
  • Egido, Jesus, Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz .– Universidad Autónoma and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Madrid, Spain
  • Gomez-Guerrero, Carmen, Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz .– Universidad Autónoma and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Madrid, Spain
  • Mezzano, Sergio A., Universidad Austral de Chile, Valdivia, Valdivia, Chile
Background

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and despite improvements in glycemic and blood pressure control by RAAS inhibitors, end-stage renal disease still remains a growing issue. Chronic inflammation plays a key role in the DN progression, but the underlying mechanisms are largely unknown. Therapeutic modulation of inflammation can be assessed by targeting soluble cytokines, their receptors or the involved cell signaling. In the BTBR ob/ob mice, a model of progressive DN that recapitulates the lesions seen in human DN, we have examined and compared the modulation of NFκB and JAK/STAT, two major inflammatory signaling pathways involved in the pathogenesis of DN. To do that we have employed inhibitory peptides targeting key domains of regulatory proteins such as Nemo-Binding Domain of IKK complex (NBD peptide) and the kinase-inhibitory region of SOCS1 (MiS1 peptidomimetic), which respectively prevent the nuclear translocation of p65 and STAT1/3 transcription factors.

Methods

Six-weeks old BTBR ob/ob mice were given intraperitoneal injections of active peptides (NBD, 6 and 10µg; MiS1, 2 and 4μg), inactive mutant peptides (10µg and 4µg, respectively) and vehicle for 7 weeks (n=6-8/group). At the end of the study, animals were sacrificed to obtain blood, urine and kidney tissue samples for further analysis.

Results

In vivo and ex vivo imaging revealed efficient peptide delivery and rapid systemic biodistribution, with selective renal metabolization in BTBR ob/ob mice. Although both active peptides significantly reduced albuminuria (ACR) in diabetic mice, a greater effect was observed with MiS1 (decrease 57% with 2µg and 66% with 4µg vs vehicle). Both NBD and MiS1 treatment improved glomerular and tubulointerstitial damage (49% with NBD and 48% with MiS1 vs vehicle) and increased the number of podocytes (46% with NBD and 55% with MiS1 vs vehicle), without changes in metabolic parameters (glycemia and lipid profile) and body weight. Additionally, high dose of MiS1 significantly reduced renal weight in compared to controls.

Conclusion

Transcriptional inhibitory peptides NBD and MiS1 significantly improve albuminuria and alleviate DN in BTBR ob/ob mice, being the inhibition of JAK/STAT pathway more effective in achieving these objectives.

Funding

  • Government Support - Non-U.S.