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Abstract: SA-PO602

Progressive Intrarenal Microvascular Damage Presents Early On and Is Preceded by Vascular Molecular Changes in ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Singha, Santu Kumar, Mayo Clinic, Rochester, Minnesota, United States
  • Abdelfattah, Ahmed, Mayo Clinic, Rochester, Minnesota, United States
  • Hanna, Christian, Mayo Clinic, Rochester, Minnesota, United States
  • Hogan, Marie C., Mayo Clinic, Rochester, Minnesota, United States
  • Chade, Alejandro R., University of Missouri, Columbia, Missouri, United States
  • Eirin, Alfonso, Mayo Clinic, Rochester, Minnesota, United States
  • Irazabal, Maria V., Mayo Clinic, Rochester, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) progression has been mainly attributed to the continuous development and expansion of kidney cysts, but the role of the intrarenal microvasculature and the mechanisms leading to vascular damage are still unclear. We hypothesized that intrarenal microvascular structural abnormalities are present from early stages and preceded by vascular molecular changes.

Methods

ADPKD (Pkd1RC/RC) and WT mice (n=16 each, 8M/8F) were studied at 1, 6, and 12 months (mo). Disease severity and progression were evaluated by kidney weight/body weight (KW/BW), body-length adjusted total kidney volume by MRI (blTKV), cystic area (CA), fibrotic area (FA), and BUN, and intrarenal microvasculature architecture by 3D (micro-CT), capillary density (H&E), and perivascular fibrosis (Trichrome). In randomly selected Pkd1RC/RC and WT kidneys (n=5, each per time point, 30 animals), mRNA-sequencing (seq) was performed to identify vasculature-related differentially expressed genes (DEGs). Transcription Factors (TFs) of the DEGs were predicted and ranked, and their gene expression examined.

Results

KW/BW, blTKV, and CA were higher in Pkd1RC/RC from 1mo, but FA and BUN were similar until 12mo. Spatial density of cortical and medullary microvessels was preserved at 1mo but progressively decreased at 6 and 12mo (Figure), associated with vessel tortuosity (vascular immaturity), capillary loss, and perivascular fibrosis. A total of 110, 48, and 201 vasculature-related genes were DE at 1, 6, and 12mo, respectively. Interactions among the Top 50 TFs involved in regulating DE vasculature-related genes in Pkd1RC/RC increased from 1 to 12mo, and the expression of 18 Top TFs followed the same pattern as their targeted genes.

Conclusion

In ADPKD, intrarenal microvasculature abnormalities are present early on and may constitute a synergistic therapeutic target. Early vascular molecular signatures may serve as biomarkers for disease progression.

Funding

  • NIDDK Support