Lipid biology of the podocyte—new perspectives offer new opportunities

Abstract

In the past 15 years, major advances have been made in understanding the role of lipids in podocyte biology. First, susceptibility to focal segmental glomerulosclerosis (FSGS) and glomerular disease is associated with an APOL1 sequence variant, is expressed in podocytes and encodes apolipoprotein L1, an important component of HDL. Second, acid sphingomyelinase-like phosphodiesterase 3b encoded by SMPDL3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from patients with recurrent FSGS. Furthermore, decreased SMPDL3b expression is associated with increased susceptibility of podocytes to injury after exposure to sera from these patients. Third, in many individuals with membranous nephropathy, autoantibodies against the phospholipase A2 (PLA2) receptor, which is expressed in podocytes, have been identified. Whether these autoantibodies affect the activity of PLA2, which liberates arachidonic acid from glycerophospholipids and modulates podocyte function, is unknown. Fourth, clinical and experimental evidence support a role for ATP-binding cassette sub-family A member 1-dependent cholesterol efflux, free fatty acids and glycerophospolipids in the pathogenesis of diabetic kidney disease. An improved understanding of lipid biology in podocytes might provide insights to develop therapeutic targets for primary and secondary glomerulopathies.

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

“…Cholesterol overload from its elevated carriers i.e . circulating LDLs, as was shown in the present study, might negatively influence the binding of podocyte SD proteins to each other, as which is assembled in lipid rafts and is playing a critical role in the formation of glomerular filtration barrier and maintenance of the interdigitating foot process pattern 42, 46, 47. We found in vivo and in vitro , SD proteins podocin and NEPH1 were dramatically decreased during the challenge of hypercholesterolaemia or ox‐LDL treatment.…”

“…Clinical and experimental studies have provided insights into the roles of lipids and lipid‐modulating proteins as key determinants of podocyte function in health and kidney diseases 42. Joles et al .…”

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

“…Unlike other members of the APOL family, APOL1 possesses a signal peptide that allows for APOL1 to be exported out of the cell and into the bloodstream, where it associates with HDL particles. APOL1 is also believed to play a role in programmed cell death and autophagy (32,33). Recently, Nichols et al (34) showed that the expression of APOL1 in podocytes and endothelial cells is induced by IFNs and Toll-like receptor agonists, suggesting a role for inflammation as a CKD inducer.…”

The Kidney in Fabry Disease

“…In Fabry disease, when the a v b 3 becomes activated, it triggers podocytic contraction and migration, finally contributing to podocyte detachment from the glomerulus and podocyturia. 19,20 Noteworthy, Utsumi et al have found elevated levels of a v b 3 integrin in the urine of individuals with Fabry disease, probably due to the accumulation of Gl3. The augmented localization of the b 3 component was seen mainly in podocytes and in epithelial cells of Bowman capsule.…”