Abstract: FR-PO999
Cadherin-11 Inhibitor SD-133 Prevents Renal Fibrosis in a Model of Tubulointerstitial Disease in Male Mice
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Davidson, Shania Ro'Shea, Georgetown University Medical Center, Washington, District of Columbia, United States
- Adapa, Sharmila, Georgetown University Medical Center, Washington, District of Columbia, United States
- Allen, Katherine C., Georgetown University Medical Center, Washington, District of Columbia, United States
- Jones, Bryce A., Georgetown University Medical Center, Washington, District of Columbia, United States
- Dial, Katelyn, Georgetown University Medical Center, Washington, District of Columbia, United States
- Myakala, Komuraiah, Georgetown University Medical Center, Washington, District of Columbia, United States
- Wang, Xiaoxin, Georgetown University Medical Center, Washington, District of Columbia, United States
- Levi, Moshe, Georgetown University Medical Center, Washington, District of Columbia, United States
Background
Fibrosis of the kidney is the last and highly morbid stage of various types of chronic kidney diseases. The progressive decline of kidney function is the result of prolonged states of inflammation and maladaptive repair mechanisms of extracellular matrix and transmembrane proteins. Cadherin-11 is transmembrane cell junction protein upregulated in various organs within fibrotic diseases, including the kidney. With this, we hypothesized that Cadherin-11 antagonism is nephroprotective in the adenine model of kidney disease.
Methods
12-week-old male 129S1/SvImJ mice were fed chow or chow supplemented with adenine (0.2% w/w) ad lib for 7 weeks. Mice were injected IP with vehicle (30% PEG-400) or Cadherin-11 antagonist SD-133 (40 mg/kg BW) 3 days per week for the duration of the study. GFR was measured in vivo by transdermal clearance of FITC-Sinistrin. Plasma and organs were later collected following euthanasia and processed for biochemical analysis.
Results
Mice fed the adenine diet had decreased body weight compared to control mice, but bodyweight was unchanged between vehicle and SD-133 treatment groups. Plasma creatinine increased with disease and was unchanged with SD-133 treatment. Additionally, there was an increase in BUN (P<0.0001), but there was no change with SD-133 treatment. In vivo measuements showed that GFR was decreased with disease (P<0.0001), but again there was no change with SD-133 treatment. However, on western blot, fibronectin and phosphorylated SMAD3 were increased with disease (p<0.001) and reduced with SD-133 treatment ( p<0.05).
Conclusion
Cadherin-11 antagonism did not exhibit beneficial kidney effects in the adenine diet model using male mice on the 129S1/SvImJ background at the 7-week timepoint as determined by BUN, plasma creatinine, and in vivo GFR measurements. However, western blots showed that Cadherin-11 antagonism reduced renal fibrosis and inhibited the pro-fibrotic SMAD3 pathway, therefore indicating that Cadherin-11 antagonism was nephroprotective in this model.
Funding
- NIDDK Support