Kidney Week

Abstract: FR-PO1069

Anti-Angiogenic Factors Increase Thrombomodulin Expression in the Kidney in Pre-eclampsia: A Role for Endothelin?

Session Information

• Glomerular Diseases: Immunology and Inflammation - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Bos, Manon, Leiden University Medical Center, Leiden, Netherlands

Manon Bos,

• Mirabito Colafella, Katrina M., Monash University, Clayton, New South Wales, Australia

Katrina M. Mirabito Colafella,

• Van der hoorn, Marie-Louise, Leiden University Medical Center, Leiden, Netherlands

Marie-Louise Van der hoorn,

• Turner, Rosanne Jane, Leiden University Medical Centre, Leiden, Netherlands

Rosanne Jane Turner,

• Bruijn, Jan A., Leiden University Medical Center, Dept.Pathology, Leiden, Netherlands

Jan A. Bruijn,

• Bloemenkamp, Kitty, Birth Centre Wilhelmina Children's Hospital,University Medical Cetre Utrecht, the Netehrlands, Leiden, Netherlands

Kitty Bloemenkamp,

• Danser, Alexander H., Erasmus Medical Center, Rotterdam, Netherlands

Alexander H. Danser,

• Van den meiracker, Anton H., Erasmus MC, Rotterdam, Netherlands

Anton H. Van den meiracker,

• Baelde, Hans J., Leiden University Medical Center, Leiden, Netherlands

Hans J. Baelde,

Background

Pre-eclampsia (PE) is a pregnancy related syndrome characterized by angiogenic imbalance, which results in symptoms such as hypertension. Furthermore, the kidney is frequently affected in PE. Similar symptoms are observed during treatment of patients with angiogenesis inhibitors like Sunitinib. Thrombomodulin is an essential endothelial regulator of inflammation and coagulation. Serum levels of the breakdown product of thrombomodulin are increased in PE. Here, we investigated thrombomodulin expression in kidneys of women with PE and hypertensive rats exposed to Sunitinib.

Methods

Renal tissue was collected from 34 pregnant women (23 controls, 11 PE) and 14 hypertensive non-pregnant women. Furthermore, kidneys were collected from male WKY rats treated with vehicle, Sunitinib (14 mg/kg/day) alone or in combination with endothelin receptor type A (ET_A) antagonist Sitaxentan (30 or 100 mg/kg/day) or non-selective ET_A/B antagonist Macitentan (30 mg/kg/day) for 8 days. Blood pressure in rats was measured by telemetry. Thrombomodulin expression was investigated with immunohistochemistry and qPCR.

Results

Glomerular thrombomodulin protein expression is increased in kidneys of women with PE compared to pregnant women and hypertensive non-pregnant women (P<0.01). Renal thrombomodulin expression originated from the glomerular vascular pole, and is not associated with other histopathologic lesions. Exposure to Sunitinib results in 1.5-times higher renal thrombomodulin mRNA expression in WKY rats (P<0.05), and Sitaxentan at both doses (P<0.001), but not macitentan, normalized this increase. Both antagonists fully prevent the Sunitinib-induced rise in blood pressure.

Conclusion

Renal thrombomodulin expression is increased both in PE and during Sunitinib mediated angiogenic inhibition. Thrombomodulin upregulation appears to be ET_A receptor-mediated, and ET_B receptors counterbalance this effect in a blood pressure-independent manner. Our data suggest that selective ET_A receptor blockade may have long-term renoprotective effects. This may also be true in patients treated with angiogenesis inhibitors.