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-PO1003

Deletion of Proximal Tubular Cell VEGF Production Promotes Renal Fibrosis: Implications for VEGF-Based Cancer Therapy

Session Information

  • Onco-Nephrology: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

Authors

  • Lin, Jamie, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Sugimoto, Hikaru, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Taduri, Gangadhar, Nizams Institute of Medical Sciences, Hyderabad, TELANGANA, India
  • Danesh, Farhad R., University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Lebleu, Valerie, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kalluri, Raghu, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Background

Targeting tumor angiogenesis by blocking VEGF (vascular endothelial growth factor) inhibits tumor development and growth, and is a common strategy in cancer therapeutics. Human and animal observations have shown that subtle changes in VEGF levels can result in hypertension, proteinuria, and glomerulopathies. VEGF deletion in all renal tubular epithelial cells has been reported to disrupt peritubular microvascularization. Since proximal tubular (PT) cells are arguably the primary target cells during kidney injury we hypothesized that loss of PT-VEGF production might provoke the development of renal fibrosis following injury.

Methods

We crossed GGT-Cre+/- mice with VEGFf/f mice to generate PT-specific VEGF knockout (GGTCre+;VEGFf/f) and control (GGTCre-;VEGFf/f) mice. Mice were challenged with unilateral ureteral obstruction (UUO) kidney injury model.

Results

PT-VEGF is dispensable for kidney development and health. No obvious histological differences including peritubular capillary assessment using CD31, an endothelial cell marker, was observed. To determine whether PT-secreted VEGF might contribute to the development of injury-induced interstitial fibrosis, both groups underwent UUO x Day 7. Increased tubular damage and interstitial fibrosis was observed in the PT-VEGF KO group compared to the control group. While there were no differences in peritubular capillary distribution in non-injured animals, segmental loss of peritubular capillaries with increased hypoxic areas was detected by carbonic anhydrase IX (hypoxia marker) staining in the PT-VEGF KO group. Furthermore, increased myofibroblasts was also observed in these animals.

Conclusion

PT-VEGF is necessary for the maintenance of the peritubular capillary network following kidney injury; preventing hypoxia, subsequent myofibroblast recruitment, and indirectly limiting renal fibrosis. Cancer patients are at high risk for developing acute kidney injury, and those on pharmacological inhibition of VEGF are even more vulnerable. These two factors alone warrant increased attention and diligence to our cancer patients who are at highest risk for progressive kidney disease and emphasize the growing importance of onco-nephrology.