ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes

Abstract

Conflict of interest: GWB, AF, and SM are inventors on pending or issued patents (US 10,183,038 and US 10,052,345) aimed at diagnosing or treating proteinuric kidney diseases. They stand to gain royalties from the future commercialization of these patents. AF is Chief Scientific Officer of L&F Health LLC and is a consultant for Variant Pharmaceuticals. Variant Pharmaceuticals has licensed worldwide rights from L&F Research to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney disease. AF is Chief Medical Officer of LipoNexT LLC. SM holds equity interest in a company presently commercializing the form of cyclodextrin referenced in this paper. AF and SM are supported by Hoffman-La Roche. AF is supported by Boehringer Ingelheim.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…In this regard, ABCA1 deficiency has been associated with the selective accumulation of cardiolipin, mitochondrial dysfunction, and subsequent podocyte lesion in DN [104]. Mitrofanova et al described the involvement of the lipid raft enzyme sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in podocyte injury by altering active sphingolipid production and reducing ceramide-1-phosphate (C1P) [104,105]. Furthermore, restoration of C1P levels was sufficient to normalize the proteinuria levels observed in a murine model of DN [106].…”

“…To restrict intrarenal lipid deposition, novel therapeutic targets have been evaluated in different preclinical models, such as ATP-binding cassette transporter A1 (ABCA1) agonists [96,99,104], renal lipoprotein lipase activators [209], Farnesoid X receptor (FXR) [210] and Liver X receptor alpha (LXRα) agonists [211], pan-TGFβ neutralizing antibodies [212,213], NF-κB inhibitors [214], fibroblast growth factor-21 therapy [215], aspirin [216], angiotensin 1-7 [217], CCR2 inhibitors [218], C5a receptor antagonists [219], cannabinoid receptor-1 blockers [220], and Nrf2 activators such as the bardoxolone methyl [171].…”

Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome

“…[1][2][3][4] We and others recently demonstrated that glomerular accumulation of cholesterol, especially cholesterol ester (CE) accumulation, occurs in experimental diabetic kidney disease (DKD) and Alport syndrome (AS). [5][6][7][8][9] These findings provide a rationale for therapeutic interventions targeting cellular cholesterol content. 10 Several inhibitors of CE transfer protein effectively increase highdensity lipoprotein cholesterol levels and have been developed for the treatment of dyslipidemia.…”

“…22,23 In previous studies, we demonstrated that the expression of adenosine triphosphate-binding cassette A1 (ABCA1), an important regulator of reverse cholesterol transport, is decreased in several glomerular disorders of nonmetabolic and metabolic origin, including AS and DKD. 5,8 In addition, these studies revealed a positive correlation between renal CE content and blood urine nitrogen in experimental models of DKD, 5 suggesting that preventing CE accumulation may Correspondence: Alessia Fornoni or Sandra Merscher, Katz Family Division of Nephrology and Hypertension and Peggy and Harold Katz Family Drug Discovery Center, University of Miami, 1580 NW 10th Ave, Miami, Florida 33136, USA. E-mail: afornoni@med.miami.edu (A. Fornoni) and smerscher@med.miami.edu (S. Merscher) prove beneficial to prevent renal lipid accumulation and improve renal disease progression.…”

Podocyte lipotoxicity in diabetic kidney disease

“…These data indicate that mitochondrial cardiolipin peroxidation promotes podocyte injury in DKD and that ABCA1 counteracts this pathogenic process. 6 In a second study published in Nature Communications, Mitrofanova et al focused on a lipid raft enzyme, sphingomyelinase-like phosphodiesterase 3b (SMPDL3b), which was previously reported to promote podocyte injury in the context of DKD or focal segmental glomerulosclerosis. 7 On the basis of the observation that SMPDL3b expression is upregulated in glomeruli from patients with DKD and in human podocytes treated with DKD sera, the authors demonstrated that SMPDL3b excess results in decreased ceramide-1-phosphate (C1P) levels and impairs an insulin-mediated prosurvival signaling pathway in human podocytes in vitro and in the kidney cortex of mice with DKD in vivo.…”