ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO760

Endothelial-Specific Phosphatase VEPTP/PTPRB Is Essential for the Development of the Renal Mesangium

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Scott, Rizaldy P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tarjus, Antoine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Carota, Isabel Anna, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Li, Yanyang, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Thomson, Benjamin R., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Onay, Tuncer, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

The angiopoietin-Tie2 signaling pathway plays an essential role in vascular development and homeostasis while its dysregulation is associated with a number of diseases including pathological neovascularization, glaucoma, diabetic nephropathy, and acute kidney injury. The endothelial-specific phosphatase VEPTP/PTPRB plays a major role in the negative regulation of Tie2 receptor phosphorylation. We genetically inactivated the Ptprb gene in mice in order to elucidate its significance in renal vascular development.

Methods

Global genetic inactivation of a conditional floxed allele of Ptprb was accomplished using a tetracycline-inducible Cre-based recombination system. Mouse kidney sections were processed for histology and immunostaining while glomerular ultrastructure was analyzed by transmission electron microscopy.

Results

Inactivation of Ptprb at E13.5 results in glomerular maldevelopment. Ptprb deficiency results in notable simplification of the glomerular tuft and glomerular aneurysms in neonatal (P0) kidneys due to the impaired establishment of the mesangium reminiscent of genetic loss of components of the PDGFB signaling system (Pdgfb, Pdgfrb, and Nrp1). Immunofluorescence for mesangial markers and ultrastructure analysis corroborate the absence of the renal mesangium in Ptprb-knockout mice. In contrast, postnatal (P0) deletion of Ptprb does not overtly affect mesangial cell recruitment but causes the development of renal capsule hemorrhages and sporadic thrombotic vascular anomalies in other organs of adult mutant animals which resemble hereditary venous malformations due to hyperactivating mutations of the Tie2 receptor in patients.

Conclusion

The renal mesangium is the de facto pericyte of the glomerular endothelium. Our findings indicate that Ptprb may play a pivotal and time-dependent role in pericyte recruitment and investment in different vascular beds. During gestation, Ptprb regulates the recruitment of mesangial cells into the glomerulus. Postnatally, Ptprb deficiency results in vascular anomalies reminiscent of venous malformations and poor pericyte investment caused by constitutive Tie2 activation.

Funding

  • NIDDK Support