APOM deficiency contributes to renal failure in glomerular diseases

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PROJECT SUMMARY Lipid-induced podocyte injury is an emerging molecular pathway contributing to the progression of glomerular diseases (GDs) of metabolic and non-metabolic origin. Research by others and us has highlighted a role for impaired reverse cholesterol transport (RCT) and altered sphingolipid metabolism in lipid-induced podocyte injury in GDs, yet, a common druggable pathway regulating both RCT and sphingolipid metabolism in podocytes remains to be identified. Among several lipoproteins, Apolipoprotein M (APOM) is mainly located in high density lipoprotein (HDL) particles where it facilitates RCT to HDL but also acts as a chaperone to transport sphingosine-1-phosphate (S1P) through the circulation. S1P signaling occurs through binding of APOM/S1P complexes to S1P receptors (S1PR1-5), which regulate many physiological processes, including migration, proliferation, and cell survival. We recently demonstrated significantly decreased glomerular APOM (gAPOM) mRNA expression in patients with GD enrolled in the NEPTUNE cohort. Our new preliminary data show that decreased gAPOM correlates with decreased plasma APOM (pAPOM), with increased glomerular sphingosine kinase 1 (SPHK1), the enzyme that converts sphingosine to S1P, and S1PR4 expression and with eGFR decline. We observed a similar gene expression pattern in Col4a3 KO mice, a mouse model of GD, and in Col4a3 KO podocytes, which was associated with glomerular/podocyte cholesterol and S1P accumulation due to impaired RCT and activation of S1P/S1PR4 signaling leading to increased apoptosis which was prevented by recombinant human APOM (rhAPOM) treatment. Importantly, the therapeutic effect of rhAPOM in preventing podocyte apoptosis in Col4a3 KO podocytes was superior to SPHK1 or S1PR4 antagonism. Finally, we demonstrate that treatment of human podocytes with exogenous S1P increases podocyte apoptosis and causes albumin leakage in a microfluid device as well as in ApoM deficient Col4a3 KO mice. Based on these observations, we hypothesize that GDs represent a state of gAPOM deficiency causing impaired RCT and activation S1P/S1PR signaling in podocytes, thereby causing lipotoxic podocyte injury. We propose a highly translational approach with three specific aims to 1) investigate if gAPOM deficiency correlates with the activation of glomerular S1P/S1PR signaling, is associated with decreased pAPOM levels and predicts outcomes in patients with GD, 2) to investigate the role of podocyte APOM deficiency on RCT and S1P/S1PR4 signaling, and 3) to investigate the therapeutic potential of recombinant human APOM in an experimental model of GD. If successful, this translational study may lead to the clinical development of APOM as a biomarker in GDs and to the use of recombinant APOM as a novel therapy for GDs.