Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice

Laeticia Scherler; Sofia N Verouti; Daniel Ackermann; Bruno Vogt; Geneviève Escher

doi:10.3390/biom12081147

Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice

Biomolecules. 2022 Aug 19;12(8):1147. doi: 10.3390/biom12081147.

Authors

Laeticia Scherler^{1

2}, Sofia N Verouti^{1

2}, Daniel Ackermann^{1

2}, Bruno Vogt^{1

2}, Geneviève Escher^{1

2}

Affiliations

¹ Department for BioMedical Research (DBMR), University of Bern, 3010 Bern, Switzerland.
² Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

Abstract

Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D₃ metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout mice. The atherosclerotic phenotype was compared to mice with normal renal function.

Methods: Mice were fed a western diet ±0.15% adenine. Urine and feces were collected to assess renal function and fecal output. Atherosclerosis, serum lipoprotein composition and functionality, hepatic lipids, and expression of genes involved in lipid metabolism, vitamin D₃ and Na⁺ homeostasis, were assessed. Bones were analyzed by microCT.

Results: Mice fed with adenine showed enhanced urinary Na⁺, Ca²⁺, and Pi excretion, reduced urinary pH, Urea_Urine/Urea_Serum, and Creatinine_Urine/Creatinine_Serum ratios. They developed less atherosclerosis. Lipoproteins in serum and hepatic lipids remained unchanged. Cholesterol efflux increased. Fecal output of cholesteryl ester and triglycerides increased. In the liver, mRNA levels of Cyp27a1, Cyp7a1, and Scarb1 increased; in the kidneys, Slc9a3, Slc12a3, Vdr, and Cyp24a1 decreased. Adenine increased cholesterol efflux in vitro. Tibias were shorter.

Conclusion: Adenine induced tubular damage and was athero-protective because of enhanced cholesterol efflux and lipids elimination in feces. Bone growth was also affected.

Keywords: atherosclerosis; cholesterol efflux; chronic kidney disease; reverse cholesterol transport; tibia.

Publication types

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

MeSH terms

Adenine* / metabolism
Animals
Atherosclerosis* / chemically induced
Atherosclerosis* / genetics
Cholesterol / metabolism
Creatinine / metabolism
Liver / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
Urea / pharmacology
Vitamin D / pharmacology

Substances

Vitamin D
Urea
Cholesterol
Creatinine
Adenine

Grants and funding

We acknowledge the support by the Swiss National Science Foundation Grant #182482, entitled “Role of vitamin D and vitamin D metabolizing enzymes in the prevention of atherosclerosis (principal investigator Geneviève Escher). Bruno Vogt is supported by the Foundation “Fonds pour la Recherche Thérapeutique”, Lausanne, Switzerland.