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

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.

Mechanisms of podocyte injury and implications for diabetic nephropathy

“…Moreover, the cardiolipin peroxidase inhibitor elamipretide ameliorates both albuminuria and podocyte loss in mice with established DN [ 257 ]. Small molecule drugs that up-regulate ABCA1-dependent cholesterol efflux by targeting oxysterol efflux by targeting oxysterol-binding protein-like 7 (OSBPL7) normalise proteinuria and prevent renal function decline in both adtiamycin-induced nephropathy and Alport Syndrome [ 289 ].…”

Molecular and Cellular Mechanisms Underlying the Initiation and Progression of Alport Glomerular Pathology

“…These compounds cause significant hearing loss in humans ( 37 ) necessitating the identification of alternate means to stimulate cholesterol efflux. Recently small molecules have been identified that activate ATP-binding cassette transporter (ABCA1)-mediated cholesterol efflux via targeting Oxysterol Binding Protein Like 7 (OSBPL7) ( 38 ). This approach also ameliorated Alport kidney disease progression and increased lifespan by about 20%.…”

Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases

“…As the major regulator of cholesterol efflux in podocytes, ABCA1 deficiency is associated with podocyte lipid accumulation in glomerular diseases such as diabetic kidney disease (DKD), FSGS and Alport syndrome [ 48 , 49 , 50 ]. Using a pharmacological ABCA1 inducer in db/db mice, we demonstrated a significant reduction in cholesterol ester content in the kidney cortices in association with improved renal function [ 48 ].…”

“…In another study, we demonstrated that promoting ABCA1-mediated cholesterol efflux similarly prevents renal disease progression in an experimental model of FSGS (adriamycin-induced nephropathy) and of Alport syndrome (Col4a3 KO mice) in association with reduced formation of lipid droplets in glomeruli and reduced accumulation of cholesterol esters in kidney cortices. Mechanistically, we showed that these compounds exercise their effect via binding to oxysterol binding protein-like 7 (OSBPL7), opening the possibility that OSBPL7 could be a novel therapeutic target [ 49 ].…”