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Kidney Week

Abstract: PO0654

Follistatin, an Activin A Antagonist in an Accelerated Mouse Model of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Bian, Xiaohui, Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
  • Conley, Sabena, Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
  • Smith, Anastasia L., Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
  • Gowan, Cody, Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
  • Snow, Zachary Kayne, Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
  • Hickson, LaTonya J., Mayo Clinic's Campus in Florida, Jacksonville, Florida, United States
Background

We previously demonstrated that circulating activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, is increased in human diabetic kidney disease (DKD) and directly correlates with kidney dysfunction. We hypothesized that follistatin, an activin A antagonist, could negate the injurious effects of activin A in DKD.

Methods

An accelerated type 2 diabetes (db/db; 10-week-old) mouse model was generated by implantation of osmotic minipumps loaded with angiotensin (Ang)-II (1000 ng/kg/min, n=14). Mice were randomized to intraperitoneal follistatin (5µg/g) or vehicle at days 15 and 18 post-pump with euthanasia at day 28. Kidney injury markers included: proteinuria, kidney injury marker (KIM)-1, tumor necrosis factor soluble receptor 1 (TNFsR1), collagen I and histological changes were measured. Kidney gene expression of activin A and macrophage chemoattractant protein-1 (MCP-1) were measured by qPCR.

Results

Implantation of AngII (dbAngII) pumps induced proteinuria, mesangial matrix expansion, glomerular sclerosis, and increased fibrosis in db/db mice compared to saline-pump controls (dbSaline; Figure 1A-D). Collagen I, TNFsR1, MCP-1, KIM-1, and activin A gene expression was increased in dbAngII mice (Figure 1E). Follistatin therapy reduced activin A gene expression and other kidney markers in addition to morphology.

Conclusion

Follistatin attenuated diabetic kidney injury, reduced activin A expression and decreased macrophage chemoattractants. Activin A may be a novel therapeutic target for halting DKD progression.

Funding

  • NIDDK Support