Lipoprotein modulation of proteinuric renal injury

Abstract

High density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain in renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, apoAI mimetic (L-4F) and in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro , primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis and the underlying signaling pathway were assessed. In vivo , we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25 + ) mice, which express human CD25 on podocytes, and podocyte injury can be induced by immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25 + :apoE−/− mice, by mating apoE-deficient (apoE−/−) mice with NEP25 + mice. Animals received L-4F or control vehicle. Renal function, podocyte injury and atherosclerosis were assessed. PAN reduced podocyte viability, migration and increased ROS production, all significantly lessened by apoAI, HDL and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/ signal transducers and activators of transcription 3. In NEP25 + mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25 + :apoE−/− mice had more atherosclerosis than non- proteinuric apoE−/− mice and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be novel candidates to lessen podocyte damage and its complications.

Preprocedural Lp(a) level and ApoB/ApoA-Ι ratio and the risk for contrast-induced acute kidney injury in patients undergoing emergency PCI

“…The uptake of ApoB by glomerular macrophages causes it to be deposited in the mesangial area of ​​the glomerulus, leading to glomerular hypertrophy and increasing transforming growth as well as the level of TGF-β, which in turn cause kidney damage [ 36 – 38 ]. ApoA-Ι can inhibit the oxidation of LDL-C, promote the reverse transport and metabolism of TC, prevent the deposition of cholesterol in the glomerulus and the recruitment of inflammatory cells in the kidney, and inhibit the occurrence of inflammation, which may have a protective effect against CI-AKI [ 39 , 40 ]. The ApoB/ApoA-Ι ratio can reflect the balance between the risk factors for and protective factors against kidney injury.…”

High-Density Lipoproteins in Kidney Disease

“…Since kidney disease is known to disrupt HDL composition and functionality it is possible that the impairment in cholesterol efflux, anti-inflammation, anti-oxidation, and anti-apoptosis capacities of HDL documented in macrophages may also affect renal cells and impact the renal response to injury [ 44 , 45 , 53 ]. Studies support this direct effect, showing that viability, migration, and ROS production in podocytes injured in vitro can be lessened by supplementation of normal apoA-I, HDL, or an apoA-I mimetic, 4F [ 68 ]. In vivo, 4F treatment significantly lessened proteinuria and preserved podocyte expression of glomerular synaptopodin and cell density in the NEP25 podocyte injury model of proteinuric kidney disease [ 68 ].…”

“…Studies support this direct effect, showing that viability, migration, and ROS production in podocytes injured in vitro can be lessened by supplementation of normal apoA-I, HDL, or an apoA-I mimetic, 4F [ 68 ]. In vivo, 4F treatment significantly lessened proteinuria and preserved podocyte expression of glomerular synaptopodin and cell density in the NEP25 podocyte injury model of proteinuric kidney disease [ 68 ]. In the mouse IgA nephropathy model, glomerular mesangial cell proliferation and matrix expansion was suppressed by apoM, an effect that was mediated by ApoM-bounded S1P [ 69 ].…”

“…Since F2-isoprostanes can directly affect renal vascular tone and stimulate eNOS activity, it is possible that HDL may ameliorate renal damage through F2-isoprostane sequestration [ 104 , 105 , 106 ]. Additionally, studies have shown that supplementation with an apoA-I mimetic reduced proteinuria, glomerular, and tubulointerstitial injury in proteinuric Nphs1-hCD25 transgenic (NEP25 + ) apoE −/− mice [ 68 ]. Together, these data indicate that normal apoA-I/HDL can benefit injured kidneys.…”

“…In addition to supplementation with normal apoA-I/HDL, targeting lipoprotein modifications or cargo is another approach to improve apoA-I/HDL functionality and thus lessen the detrimental effects on renal parenchymal cells. For example, pentylpyridoxamine (PPM) reduces IsoLG modification of apoA-I/HDL and has been shown to significantly reduce experimental proteinuria, tubular injury, and lymphangiogenesis ( Figure 1 , steps 2–5) [ 68 ]. In human subjects, we showed that IL-1 blockade improved HDL functionality in patients with pre-dialysis CKD as well as individuals on maintenance hemodialysis [ 109 ].…”