Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease

Annelie Falkevall; Annika Mehlem; Isolde Palombo; Benjamin Heller Sahlgren; Lwaki Ebarasi; Liqun He; A Jimmy Ytterberg; Hannes Olauson; Jonas Axelsson; Birgitta Sundelin; Jaakko Patrakka; Pierre Scotney; Andrew Nash; Ulf Eriksson

doi:10.1016/j.cmet.2017.01.004

Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease

Cell Metab. 2017 Mar 7;25(3):713-726. doi: 10.1016/j.cmet.2017.01.004. Epub 2017 Feb 9.

Authors

Affiliations

¹ Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
² 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.
³ Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
⁴ 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.
⁵ Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
⁶ 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.
⁷ Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden.
⁸ KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 57 Huddinge, Sweden.
⁹ CSL Limited, Parkville, VIC 3052, Australia.
¹⁰ Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: ulf.pe.eriksson@ki.se.

PMID: 28190774
DOI: 10.1016/j.cmet.2017.01.004

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.

Keywords: albuminuria; diabetic kidney disease; endothelial fatty acid transport; insulin signaling; lipotoxicity; podocytes; renal steatosis; vascular endothelial growth factor B.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Albuminuria / complications
Albuminuria / metabolism
Albuminuria / pathology
Animals
Antibodies, Neutralizing / administration & dosage
Antibodies, Neutralizing / pharmacology
Diabetes Mellitus, Experimental / complications
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Diabetes Mellitus, Type 1 / complications
Diabetes Mellitus, Type 1 / metabolism
Diabetes Mellitus, Type 1 / pathology
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Diabetic Nephropathies / metabolism*
Diabetic Nephropathies / pathology
Diabetic Nephropathies / prevention & control*
Disease Models, Animal
Disease Progression
Dyslipidemias / complications
Dyslipidemias / metabolism
Dyslipidemias / pathology
Fatty Acid Transport Proteins / metabolism
Female
Gene Deletion
Humans
Insulin / pharmacology
Kidney / drug effects
Kidney / metabolism
Kidney / pathology*
Kidney / physiopathology
Lipids / toxicity*
Male
Mice, Inbred C57BL
Middle Aged
Podocytes / drug effects
Podocytes / metabolism
Podocytes / pathology
Signal Transduction* / drug effects
Up-Regulation / drug effects
Vascular Endothelial Growth Factor B / metabolism*
Young Adult

Substances

Antibodies, Neutralizing
Fatty Acid Transport Proteins
Insulin
Lipids
Slc27a4 protein, mouse
Vascular Endothelial Growth Factor B