Anti-VEGF antibody treatment accelerates polycystic kidney disease.

Abstract

Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1α and -2α expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1α and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1α levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease.

• Authors: Shagun Raina, Michael Honer, Stefanie D Krämer, Yang Liu, Xueqi Wang, Stephan Segerer, Rudolf P Wüthrich, Andreas L Serra
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 301 Issue 4 Pg. F773-83 (Oct 2011) ISSN: 1522-1466 [Electronic] United States
• PMID: 21677148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• fluoromisonidazole
• endothelial PAS domain-containing protein 1
• Misonidazole

Topics

• Animals
• Antibodies, Neutralizing (adverse effects, therapeutic use)
• Basic Helix-Loop-Helix Transcription Factors (biosynthesis)
• Cell Proliferation
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Male
• Misonidazole (analogs & derivatives)
• Organ Size
• Polycystic Kidney Diseases (diagnostic imaging, pathology, therapy)
• Proteinuria (metabolism, physiopathology)
• Radionuclide Imaging
• Rats
• Rats, Sprague-Dawley
• Renal Insufficiency (immunology, pathology, therapy)
• Severity of Illness Index
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, immunology)