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

Patricia G. Wilson, Joel C. Thompson, Meghan H. Yoder, Richard Charnigo, Lisa R. Tannock

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)2264-2274
Number of pages11
JournalJournal of Lipid Research
Volume58
Issue number12
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This work was supported by US Department of Veterans Affairs Merit Review Award BX000622 to L.R.T. and cores supported by National Institutes of Health Grant P30 GM103527. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the US Department of Veterans Affairs, the National Institutes of Health, or the United States Government. Manuscript received 2 June 2017 and in revised form 11 September 2017. Published, JLR Papers in Press, September 14, 2017 DOI https://doi.org/10.1194/jlr.M078204

Keywords

  • Apolipoprotein B
  • Biglycan
  • Cholesterol
  • Diabetes
  • Extracellular matrix
  • Kidney
  • Proteoglycans
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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