Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease

Nat Commun. 2021 Aug 2;12(1):4662. doi: 10.1038/s41467-021-24890-3.

Abstract

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Biological Transport / drug effects
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Diabetic Nephropathies / metabolism*
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Mice, 129 Strain
  • Mice, Knockout
  • Molecular Structure
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Organic Chemicals / chemical synthesis
  • Organic Chemicals / chemistry
  • Organic Chemicals / pharmacology*
  • Podocytes / cytology
  • Podocytes / metabolism*
  • Proteinuria / metabolism*
  • RNA Interference
  • Receptors, Steroid / antagonists & inhibitors*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • THP-1 Cells

Substances

  • ATP Binding Cassette Transporter 1
  • Organic Chemicals
  • Receptors, Steroid
  • oxysterol binding protein
  • Niacinamide
  • Cholesterol