Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Reducing VEGF-B signalling ameliorates renal lipotoxicity and protects against diabetic kidney disease (#39)

Pierre Scotney 1 , Annelie Falkevall 2 , Annika Mehlem 2 , Isolde Palombo 2 , Benjamin H Sahlgren 2 , Lwaki Ebarasi 2 3 4 , Liqun He 3 , Jimmy A Ytterberg 5 6 , Hannes Olauson 4 , Jonas Axelsson 2 7 , Birgitta Sundelin 8 , Jaakko Patrakka 9 , Andrew Nash 1 , Ulf Eriksson 2
  1. Research, CSL Limited, Parkville, Victoria, Australia
  2. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  3. Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
  4. Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
  5. Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  6. Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  7. Center for Apheresis and Stem Cell Handling, Karolinska University Hospital, Stockholm, Sweden
  8. Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  9. KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden

Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanisms underlying this observation and to what extent they contribute to disease progression are unknown.

Vascular endothelial growth factor B (VEGF-B) has been shown to control muscle lipid accumulation through regulation of trans-endothelial fatty acid transport  (Hagberg et al., 2012). VEGF-B expression is under control of PGC1α, a regulator of mitochondrial energy metabolism and ERR-α, the estrogen-related receptor α (Mehlem et al., 2016). In experimental mouse models of DKD (db/db mice) renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signalling in DKD mouse models, either by Vegfb gene deletion in db/db mice or targeting VEGF-B with an antagonist antibody in db/db, high fat diet and streptozotocin treated mice, reduces renal lipotoxicity, re-sensitizes podocytes to insulin signalling, inhibits the development of DKD-associated pathologies (glomerular mesangial expansion, glomerular sclerosis and podocyte loss), and prevents renal dysfunction (Falkevall et al., 2017). Elevated VEGF-B levels are found in the glomeruli of patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.

  1. Hagberg, C. E., Mehlem, A., Falkevall, A., Muhl, L., Fam, B. C., Ortsater, H., Scotney, P., Nyqvist, D., Samen, E., Lu, L., Stone-Elander, S., Proietto, J., Andrikopoulos, S., Sjoholm, A., Nash, A., & Eriksson, U. (2012). Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature, 490(7420), 426-430. doi: 10.1038/nature11464
  2. Mehlem, A., Palombo, I., Wang, X., Hagberg, C. E., Eriksson, U., & Falkevall, A. (2016). PGC-1alpha Coordinates Mitochondrial Respiratory Capacity and Muscular Fatty Acid Uptake via Regulation of VEGF-B. Diabetes, 65(4), 861-873. doi: 10.2337/db15-1231
  3. Falkevall, A., Mehlem, A., Palombo, I., Heller Sahlgren, B., Ebarasi, L., He, L., Ytterberg, A. J., Olauson, H., Axelsson, J., Sundelin, B., Patrakka, J., Scotney, P., Nash, A., & Eriksson, U. (2017). Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease. Cell Metab, 25(3), 713-726. doi: 10.1016/j.cmet.2017.01.004