title: Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease.
abstract: 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 mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Falkevall
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Mehlem
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Isolde
authors.initials: I
authors.lastname: Palombo
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Heller Sahlgren
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Lwaki
authors.initials: L
authors.lastname: Ebarasi
authors.affiliation: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: A Jimmy
authors.initials: AJ
authors.lastname: Ytterberg
authors.affiliation: Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Center for Apheresis and Stem Cell Handling, Karolinska University Hospital, 141 86 Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Axelsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sundelin
authors.affiliation: KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Patrakka
authors.affiliation: CSL Limited, Parkville, VIC 3052, Australia.
authors.forename: Pierre
authors.initials: P
authors.lastname: Scotney
authors.affiliation: CSL Limited, Parkville, VIC 3052, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nash
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: ulf.pe.eriksson@ki.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D050171:Dyslipidemias / Q000150:complications / Q000378:metabolism / Q000473:pathology; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008055:Lipids / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D050612:Fatty Acid Transport Proteins; D007328:Insulin; D008055:Lipids; C493572:Slc27a4 protein, mouse; D042561:Vascular Endothelial Growth Factor B
keywords: albuminuria; diabetic kidney disease; endothelial fatty acid transport; insulin signaling; lipotoxicity; podocytes; renal steatosis; vascular endothelial growth factor B