Prevention of renal apoB retention is protective against diabetic nephropathy: role of TGF-β inhibition.

Abstract

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr-/- mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective.

• Authors: Patricia G Wilson, Joel C Thompson, Meghan H Yoder, Richard Charnigo, Lisa R Tannock
• Journal: Journal of lipid research (J Lipid Res) Vol. 58 Issue 12 Pg. 2264-2274 (12 2017) ISSN: 1539-7262 [Electronic] United States
• PMID: 28912302 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antibodies, Neutralizing
• Apob protein, mouse
• Apolipoprotein B-100
• Apolipoproteins B
• Biglycan
• Receptors, LDL
• Transforming Growth Factor beta
• Streptozocin

Topics

• Albuminuria (drug therapy, genetics, metabolism, pathology)
• Animals
• Antibodies, Neutralizing (pharmacology)
• Apolipoprotein B-100
• Apolipoproteins B (genetics, metabolism)
• Biglycan (deficiency, genetics)
• Diabetes Mellitus, Experimental (chemically induced, drug therapy, genetics, metabolism)
• Diabetic Nephropathies (drug therapy, genetics, metabolism, pathology)
• Diet, High-Fat (adverse effects)
• Kidney (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, LDL (deficiency, genetics)
• Streptozocin
• Survival Analysis
• Transforming Growth Factor beta (antagonists & inhibitors, genetics, metabolism)