Kidney Week

Abstract: TH-OR70

Aberrant Renal Microvascular Remodelling and Impaired Blood Perfusion Occur in the Early Stages of Autosomal Dominant Polycystic Kidney Disease

Session Information

• Investigations in Polycystic and Tubulointerstitial Kidney Diseases
  November 02, 2023 | Location: Room 105, Pennsylvania Convention Center
  Abstract Time: 05:51 PM - 06:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Jafree, Daniyal J., University College London, London, United Kingdom

Daniyal J. Jafree, MBBS, PhD

• Perera, Charith, University College London, London, United Kingdom

Charith Perera,

• Pomeranz, Gideon, University College London, London, United Kingdom

Gideon Pomeranz,

• Wilson, Laura, University College London, London, United Kingdom

Laura Wilson,

• Mason, William John, University College London, London, United Kingdom

William John Mason,

• Joannou, Maria K., University College London, London, United Kingdom

Maria K. Joannou,

• Muto, Yoshiharu, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Yoshiharu Muto,

• Humphreys, Benjamin D., Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Benjamin D. Humphreys,

• Lythgoe, Mark, University College London, London, United Kingdom

Mark Lythgoe,

• Walker-Samuel, Simon, University College London, London, United Kingdom

Simon Walker-Samuel,

• Long, David A., University College London, London, United Kingdom

David A. Long,

Background

The renal microvasculature is altered in autosomal dominant polycystic kidney disease (ADPKD); assumed to be a secondary consequence of expanding fluid-filled cysts. However, the vascular phenotype may be an important contributor from the initiation of PKD. Therefore, we assessed the molecular profile, structure, and function of the renal microvasculature in the early stages of ADPKD.

Methods

We amassed single nucleus RNA-seq (snRNA-seq) data of microvasculature from human ADPKD explants, validating findings using 3D confocal microscopy. A time-course of murine PKD carrying an orthologous mutation (p.R3269C) in Pkd1 (Pkd1^RC/RC) was generated by assessing kidney:body weight ratio and blood urea nitrogen. Arterial spin labelling (ASL) and 3D confocal microscopy were leveraged to examine renal blood flow and microvascular structure at early (3 months) and late (9 months) timepoints in the Pkd1^RC/RC murine model.

Results

A population of osteopontin (SPP1)⁺ vessels was identified in pericystic regions of human ADPKD, but not in human kidney disease of other etiologies. Endothelial SPP1 was upregulated in mice at 3 months of age; long before kidney function declined in the mouse model. This was associated with reduction in renal blood flow in non-cystic regions of cortex of Pkd1^RC/RC mice compared to controls at both 3 months (p = 0.005) and 9 months (p = 0.004) of age. In 3-month-old Pkd1^RC/RC mice, abnormal microvascular patterning was found, including decrease in mean vessel length (p = 0.04) and increased vascular density (p = 0.01).

Conclusion

Multiple modalities applied to mouse and human tissues suggest that microvascular molecular profile, structure and function are altered in ADPKD prior to irreversible loss of renal function. Our findings advocate the renal microvasculature in ADPKD as a therapeutic target, with the potential to modulate or preserve organ function from early stages of the disease.

Funding

• Government Support – Non-U.S.