Abstract: FR-PO714

Down Regulation of Gamma-Adducin Diminishes Glomerular Function and Promotes Hypertension Related CKD

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • He, Xiaochen, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Fan, Fan, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Poudel, Bibek, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Wang, Shaoxun, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Mims, Paige N, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Roman, Richard J., University of Mississippi Medical Center, Jackson, Mississippi, United States
Background

Fawn Hooded Hypertensive (FHH) rat is a genetic model of hypertension-induced chronic kidney disease (CKD). Using overlapping Chr 1 congenic strains, we identified a K572Q mutation in Add3 as a positional candidate gene for proteinuria in FHH rats. The present study examined whether knockin of wild type Add3 alters the development of proteinuria and hypertension induced renal injury in FHH rats.

Methods

Blood pressure and proteinuria were evaluated weekly in FHH and FHH. Add3 transgenic rats as they aged from 12 to 24 weeks of age or during the development of DOCA/salt induced hypertension. Renal injury was assessed by histology analysis. In vitro, Add3 was knocked down in normal rat kidney epithelial cells, a model system of podocyte, by using 27-mer Dicer-substrate RNAi, followed by MTS assay, F-actin immunostaining, or mitochondrial function assay.

Results

Blood pressure was similar in FHH and FHH. Add3 transgenic rats. Proteinuria increased from 37±2 to 260±32 mg/day as they aged in FHH rats (n=30), but this increase was attenuated in FHH.Add3 transgenic rats (24±3 to 170±16 mg/day, n=12). Moreover, DOCA hypertensive FHH rats (484±78 mg/day, n=21) exhibited more severe proteinuria than that seen in FHH.Add3 transgenic rats (259±5 mg/day, n=12). DOCA hypertensive FHH rats developed more severe renal injury than hypertensive FHH.1BN and FHH.Add3 transgenic rats that express wt-Add3. The glomerular injury score averaged 3.31±0.01 in FHH versus 2.54±0.01 and 2.50±0.03, in FHH.1BN and FHH.Add3 rats. The percentage of fibrosis in the renal cortex and vascular remodeling were significantly higher in DOCA treated hypertensive FHH rats than in FHH.1BN and FHH.Add3 transgenic rats. In normal rat kidney epithelial cells, down-regulation of Add3 decreased cell proliferation by 50%, disrupted the actin cytoskeleton, and impaired mitochondrial function.

Conclusion

These results suggest that down regulation of Add3 may decrease glomerular function in FHH rats by disrupting the actin cytoskeleton and impairing mitochondrial function of podocytes, which may contribute to the development of renal end organ damage with aging and after the onset of hypertension.

Funding

  • NIDDK Support