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PCSK9对足细胞脂质稳态和细胞损伤的作用及机制
吴美延, 陈志, 臧崇森, 马福哲, 侯洁, 许钟镐
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PCSK9对足细胞脂质稳态和细胞损伤的作用及机制
Effect and mechanism of PCSK9 on lipid homeostasis and cell damage of podocytes
目的 探讨前蛋白转化酶枯草杆菌蛋白酶9（proprotein convertase subtilisin/kexin type 9，PCSK9）对足细胞脂质稳态和细胞损伤的影响及其作用机制。 方法 选取12周龄C57BL/6野生型小鼠（对照组，n=10）和系统性敲除PCSK9基因型小鼠（PCSK9 KO组，n=10）为动物模型，经心脏全身灌注后取肾组织。体外培养小鼠足细胞，用干扰小RNA（siRNA）敲低足细胞PCSK9的表达。用荧光染料BODIPY 493/503染色法观察小鼠肾组织肾小球及体外培养足细胞内的脂质蓄积程度；透射电子显微镜观察足细胞的足突、线粒体结构和脂滴大小及其分布；TUNEL染色法评估肾小球内的细胞凋亡；实时荧光定量PCR（qPCR）和Western印迹法检测线粒体功能相关关键酶过氧化物酶体增殖物激活受体C辅激活因子1α（peroxisome proliferator-activated receptor-C coactivator 1α，PGC-1α）、肉毒碱棕榈酰转移酶1（carnitine palmitoyltransferase 1，CPT-1）、乙酰辅酶A氧化酶1（acetyl CoA oxidase 1，Acox-1），以及凋亡相关指标的mRNA和蛋白表达水平。 结果 与对照组相比，PCSK9 KO组小鼠肾小球内脂质蓄积更显著；肾组织内线粒体功能相关关键酶PGC-1α蛋白和mRNA相对表达量均显著降低，CPT-1和Acox-1的mRNA相对表达量也均显著降低（均P<0.05）；肾小球足细胞内线粒体肿胀、嵴消失，足细胞的足突部分融合、消失；肾小球内细胞凋亡指数增加（P<0.05）。与对照组比较，体外培养的PCSK9 siRNA组足细胞内脂质蓄积显著，线粒体功能相关关键酶PGC-1α、CPT-1和Acox-1的mRNA相对表达量下降，线粒体结构受损，细胞凋亡指数增加（均P<0.05）。 结论 PCSK9 参与足细胞的脂代谢平衡，PCSK9 表达减少增加足细胞内脂质沉积，诱导线粒体结构及功能受损，导致细胞凋亡。
Objective To evaluate the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on lipid homeostasis and cellular injury of podocytes, and to clarify its mechanism. Methods Twelve-week old C57BL/6 wild-type mice (n=10) and PCSK9 knockout (PCSK9 KO) mice (n=10) were selected as the animal models. The renal tissues were taken after perfusion through heart. Mouse podocytes were transfected with PCSK9 siRNA to downregulate PCSK9 expression. BODIPY 493/503 staining was performed for evaluating lipid accumulation, and standard transmission electron microscopy (TEM) was used to observe the foot process of podocytes, the shape of mitochondria and lipid droplet in podocytes. TUNEL staining was carried out to evaluate cell apoptosis in glomerulus. The parameters about mitochondria function (key enzymes such as PGC-1α, CPT-1 and Acox-1) and apoptosis were quantified through qPCR and western blotting. Results The lipid accumulation in glomerulus of PCSK9 KO mice were more serious than controls. The expression of PGC-1α protein and PGC-1α, CPT-1 and Acox-1 mRNA in PCSK9 KO mouse kidney tissues were decreased than controls (all P<0.05), and mitochondria swelling and cristae disappearance in podocytes of PCSK9 KO mice were observed. In PCSK9 KO group, the foot process of podocytes partially fused and disappeared, and the apoptosis index increased compared with the control group (P<0.05). In vitro, compared with the control group, the lipid accumulation was more significant, transcription level of key enzymes related to mitochondrial function was decreased, mitochondrial structure was damaged and the apoptosis index was increased in cultured podocyte PCSK9 siRNA group (all P<0.05). Conclusions PCSK9 is involved in the lipid homeostasis of podocytes. The decrease of PCSK9 results in the increase of intracellular lipid accumulation, accompanied by the mitochondrial structure damage and disfunction of podocytes, and leads to cell apoptosis.
足细胞 / 线粒体 / 脂代谢障碍 / 脂质沉积 / 前蛋白转化酶枯草杆菌蛋白酶9 / 凋亡 {{custom_keyword}} /
Podocytes / Mitochondria / Lipid metabolism disorders / Lipid deposition / Proprotein convertase subtilisin/kexin type 9 / Apoptosis {{custom_keyword}} /
孙玉玲 , {{custom_editor}}
表1 各基因引物序列 |
| 基因名称 | 上游引物序列 | 下游引物序列 |
|---|---|---|
| PCSK9 | 5'-AGTAGCAGTGACCTGTTGGG-3' | 5'-TGGGCGAAGACAAAGGAGTC-3' |
| PGC-1α | 5'-AGTCCCATACACAACCGCAG-3' | 5'-CCCTTGGGGTCATTTGGTGA-3' |
| CPT-1 | 5'-GGTCTTCTCGGGTCGAAAGC-3' | 5'-TCCTCCCACCAGTCACTCAC-3' |
| Acox-1 | 5'-CTTGGATGGTAGTCCGGAGA-3' | 5'-TGGCTTCGAGTGAGGAAGTT-3' |
| Bax | 5'-TCCACCAAGAAGCTGAGCGAG-3' | 5'-GTCCAGCCCATGATGGTTCT-3' |
| Bcl-2 | 5'-TGGGATGCCTTTGTGGAACT-3' | 5'-CAGCCAGGAGAAATCAAACAGA-3' |
| 18S rRNA | 5'-AACTAAGAACGGCCATGCAC-3' | 5'-CCTGCGGCTTAATTTGACTC-3' |
| 注：PCSK9：前蛋白转化酶枯草溶菌素9；PGC-1α：过氧化物酶体增殖物激活受体激活因子1α；CPT-1：肉毒碱棕榈酰转移酶1；Acox-1：乙酰辅酶A氧化酶1；Bax：Bcl-2相关X蛋白；Bcl-2：B淋巴细胞瘤2；18S rRNA：内参照基因 |
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Oxidized lipids initiate and modulate the inflammatory cellular events in the arterial wall and the formation of macrophage foam cells. CD36 mediates the cellular uptake of ox-LDL through its recognition of specific truncated fatty acid moieties and oxidized phosphatidylcholine. Evidence has been reported that chemokine CXCL16, rather than CD36, is the main scavenger receptor in human podocytes mediating the uptake of ox-LDL. Ox-LDL induces loss of nephrin expression from cultured podocytes. It has been recently shown that nephrin once phosphorilated associates with PI3K and stimulates the Akt dependent signaling. This pathway plays a critical role in nephrin-actin-dependent cytoskeleton activation and remodeling, in the control of protein trafficking and in podocyte survival. An enhanced FFA uptake by podocytes is mediated by increased C36 scavenger receptor expression, together with a decrease of betaoxidation and in turn intracellular lipid accumulation. Accumulated FFA that is trapped into the mitochondrial matrix leads to mitochondrial ROS production, lipid peroxidation and mitochondrial damage and dysfunction. A disturbed transport and oxidation of FFA, paralleled by an impaired antioxidant response, damages podocyte structure and leads to glomerulopathy in early stages of nephrosis. Increased triglyceride synthesis and ox-and glycated LDL uptake by mesangial cells may also contribute to determine diabetic glomerulopathy. Oxidative processes are pivotal events in injury to renal tubular and epithelial cells exposed to ox-LDL. Notably CXCL16 are the main receptors for the uptake of ox-LDL in podocytes, whereas CD36 plays this role in tubular renal cells. In overt type 2 diabetes Ox-LDL and FFA damage podocyte function, SD-podocyte structure and tubulointerstitial tissue, at least partially, through different pathogenetic mechanisms. Further studies are needed to investigate the role of Ox-LDL and FFA on renal complications in obese, insulin resistant patients before the development of diabetes. The aim of the present review is to briefly elucidate the patterns of systemic lipid metabolism and the individual effects of lipotoxicity at glomerular and tubular level in the kidney of overt type 2 diabetic patients. These findings better elucidate our knowledge of diabetic glomerulopathy, beside and along with previous findings, in vivo and in vitro, on ox-LDL and FFA effects in mesangial cells.Copyright © 2010 Elsevier B.V. All rights reserved.
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The proprotein convertase PCSK9 gene is the third locus implicated in familial hypercholesterolemia, emphasizing its role in cardiovascular diseases. Loss of function mutations and gene disruption of PCSK9 resulted in a higher clearance of plasma low density lipoprotein cholesterol, likely due to a reduced degradation of the liver low density lipoprotein receptor (LDLR). In this study, we show that two of the closest family members to LDLR are also PCSK9 targets. These include the very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) implicated in neuronal development and lipid metabolism. Our results show that wild type PCSK9 and more so its natural gain of function mutant D374Y can efficiently degrade the LDLR, VLDLR, and ApoER2 either following cellular co-expression or re-internalization of secreted human PCSK9. Such PCSK9-induced degradation does not require its catalytic activity. Membrane-bound PCSK9 chimeras enhanced the intracellular targeting of PCSK9 to late endosomes/lysosomes and resulted in a much more efficient degradation of the three receptors. We also demonstrate that the activity of PCSK9 and its binding affinity on VLDLR and ApoER2 does not depend on the presence of LDLR. Finally, in situ hybridization show close localization of PCSK9 mRNA expression to that of VLDLR in mouse postnatal day 1 cerebellum. Thus, this study demonstrates a more general effect of PCSK9 on the degradation of the LDLR family that emphasizes its major role in cholesterol and lipid homeostasis as well as brain development.
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Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery. The PCSK9 saga is unfolding quickly but is far from complete. Here, we review major scientific understandings as they relate to the role of PCSK9 in lipoprotein metabolism and atherosclerotic cardiovascular disease and the impact that therapies designed to inhibit its action are having in the clinical setting.© 2018 American Heart Association, Inc.
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Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic low-density lipoprotein (LDL)-cholesterol levels. Although PCSK9 is mainly of hepatic origin, extra-hepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression.In the present study we show that, among vascular cells, PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, macrophages and monocytes. PCSK9 was also detectable in human atherosclerotic plaques. Conditioned media from SMCs significantly reduced LDLR expression in human macrophage and in the macrophage cell line J774. Co-culture experiments also demonstrated the influence of SMCs on LDLR expression in J774. PCSK9 released from SMCs directly regulated LDLR expression in macrophages as demonstrated by retroviral overexpression or knockdown of PCSK9 with small interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic activity of PCSK9 was not required for LDLR downregulation since cultured media containing either the catalytic inactive PCSK9 or PCSK9 WT had a similar effect on LDLR in J774. Finally, conditioned media from SMCs affected β-VLDL cholesterol uptake and PCSK9 expression reduced both LDLR and LDL uptake in J774.Taken together our data indicate that PCSK9 secreted by human SMCs is functionally active and capable of reducing LDLR expression in macrophages. A possible direct role for this protein in foam cell formation and atherogenesis is suggested.Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet beta cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4 months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets.Copyright 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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吴美延, 臧崇森, 马福哲, 等. PCSK9对C57BL/6小鼠肾组织脂质平衡及损伤的作用[J]. 中华肾脏病杂志, 2018, 34(11): 845-850. DOI: 10.3760/cma.j.issn.1001-7097.2018.11.007.
目的 评估PCSK9（proprotein convertase subtilisin kexin type 9）对C57BL/6小鼠肾脏组织脂质平衡的影响以及损伤作用。 方法 12周龄的C57BL/6野生型小鼠和系统性敲除PCSK9基因小鼠通过代谢笼收集24 h尿，经心全身灌注，取出肾脏。采用ELISA方法检测尿微量白蛋白、血尿肌酐、血总胆固醇、肾组织内总胆固醇和甘油三酯水平，BODIPY 493/503染色，透射电镜（TEM）观察肾组织内脂质蓄积；PAS染色、TUNNEL染色以及qPCR和Western印迹法评估肾组织损伤及细胞凋亡。 结果 与C57BL/6野生型对照组相比，PCSK9 KO组肾组织内总胆固醇及甘油三酯水平升高（均P＜0.05），BODIPY 493/503染色显示肾小球及肾小管细胞内脂质染色明显加深，TEM提示肾小管细胞内脂滴数目显著增多。系统性敲除PCSK9基因小鼠较C57BL/6野生型对照组尿微量白蛋白/尿肌酐升高（P＜0.05），Podocin和Nephrin的转录水平下降（均P＜0.05），TEM可见肾小球内足细胞足突变短、不同程度的融合。与野生型对照组相比，PCSK9 KO组小鼠肾组织内Bax和Cleaved Caspase 3表达升高，Bcl-2表达下降（均P＜0.05）。 结论 PCSK9表达下降增加肾组织细胞内脂质蓄积，继而诱导肾固有细胞的损伤和凋亡。
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朱雪玲, 曹英杰, 刘静, 等. EP1受体通过激活p38 MAPK通路介导阿霉素诱导的足细胞损伤[J]. 中华肾脏病杂志, 2018, 34(7): 539-549. DOI: 10.3760/cma.j.issn.1001-7097.2018.07.010.
目的 探讨前列腺素E2受体1亚型（EP1）在阿霉素（ADR）诱导的足细胞损伤中的作用及其可能机制。 方法 （1）动物实验：6～8周龄雄性Balb/c小鼠被随机分为4组：对照组；ADR组；EP1激动剂（17-phenyl PGE2）+ADR组；EP1拮抗剂（SC-19220）+ADR组。尾静脉注射ADR（10 mg/kg）构建小鼠肾病综合征模型，分别给予EP1激动剂（1 μg/g）和拮抗剂（25 μg/g）。检测小鼠尿蛋白量、血生化、肾脏病理改变、电镜下足细胞改变以及足细胞相关蛋白的表达变化。（2）细胞实验：体外培养足细胞，分为4组：对照组；ADR组；EP1激动剂+ADR组；EP1拮抗剂+ADR组。CCK-8法检测足细胞增殖情况；ELISA 法检测足细胞前列腺素E2（PGE2）含量；间接免疫荧光法检测足细胞相关蛋白nephrin、podocin、CD2AP在足细胞中的定位；实时定量PCR法及Western 印迹法检测足细胞相关蛋白mRNA 及蛋白的表达；Western 印迹法检测p38 MAPK活性变化；流式细胞术检测细胞凋亡。 结果 （1）动物实验结果：与对照组相比，ADR组小鼠出现明显蛋白尿、血生化及肾脏病理改变；与ADR组相比，EP1激动剂+ADR组尿蛋白量增多、血生化异常及肾脏病理改变加重，拮抗剂+ADR组上述改变减轻。免疫组化结果显示，ADR组足细胞相关蛋白nephrin、podocin、CD2AP表达与对照组相比显著降低，EP1激动剂可进一步抑制其表达，拮抗剂干预后上述改变得到改善（均P＜0.05）。电镜下观察ADR组足细胞足突增宽、融合，激动剂组足细胞损伤进一步加重，拮抗剂干预后足细胞损伤减轻。（2）细胞实验结果：与对照组相比，ADR组足细胞中PGE2含量、环氧合酶 2（COX2）mRNA及蛋白表达增加，nephrin、podocin、CD2AP mRNA及蛋白表达下降，p38 MAPK活性增加，足细胞凋亡显著增多（均P＜0.05）。EP1激动剂干预后上述改变加重（均P＜0.05）；拮抗剂可下调PGE2及COX2 mRNA及蛋白的表达，上调nephrin、podocin、CD2AP mRNA及蛋白表达，抑制p38 MAPK活性，抑制足细胞凋亡（均P＜0.05）。加入p38 MAPK抑制剂（10 μmol/L）可以减轻EP1激动剂对足细胞相关蛋白nephrin、podocin、CD2AP表达的抑制作用。 结论 EP1受体可能通过激活p38 MAPK信号通路抑制足细胞相关蛋白nephrin、podocin、CD2AP的表达，介导ADR诱导的足细胞损伤，抑制EP1受体对足细胞有保护作用。
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\n The prohibitin (PHB)-domain proteins are membrane proteins that regulate a variety of biological activities, including mechanosensation, osmotic homeostasis, and cell signaling, although the mechanism of this regulation is unknown. We have studied two members of this large protein family, MEC-2, which is needed for touch sensitivity in\n Caenorhabditis elegans\n, and Podocin, a protein involved in the function of the filtration barrier in the mammalian kidney, and find that both proteins bind cholesterol. This binding requires the PHB domain (including palmitoylation sites within it) and part of the N-terminally adjacent hydrophobic domain that attaches the proteins to the inner leaflet of the plasma membrane. By binding to MEC-2 and Podocin, cholesterol associates with ion-channel complexes to which these proteins bind: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. Both the MEC-2-dependent activation of mechanosensation and the Podocin-dependent activation of TRPC channels require cholesterol. Thus, MEC-2, Podocin, and probably many other PHB-domain proteins by binding to themselves, cholesterol, and target proteins regulate the formation and function of large protein–cholesterol supercomplexes in the plasma membrane.\n
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Podocytes are visceral epithelial cells supporting the function of the glomerular filter. Interdigitating foot processes of podocytes enwrap the glomerular capillaries and are connected by a highly specialized cell junction, the slit diaphragm. Signal transduction at the slit diaphragm is essential for the proper function of the kidney filtration barrier. The slit diaphragm constitutes a dynamic multiprotein signaling complex that contains structural proteins, receptors, signaling adaptors, ion channels, and scaffolding proteins. Function of some of these proteins requires cholesterol attached to the multiprotein complex. Recruitment of cholesterol is achieved through the PHB domain protein podocin, a member of a novel family of lipid-binding proteins that are conserved through evolution. The finding that cholesterol interaction regulates the activity of ion channels at the glomerular filtration barrier has important implications for renal physiology and pathophysiology.
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Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD(+)) when compared with diabetic patients with normoalbuminuria (DKD(-)) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.
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Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic low-density lipoprotein (LDL)-cholesterol levels. Although PCSK9 is mainly of hepatic origin, extra-hepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression.In the present study we show that, among vascular cells, PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, macrophages and monocytes. PCSK9 was also detectable in human atherosclerotic plaques. Conditioned media from SMCs significantly reduced LDLR expression in human macrophage and in the macrophage cell line J774. Co-culture experiments also demonstrated the influence of SMCs on LDLR expression in J774. PCSK9 released from SMCs directly regulated LDLR expression in macrophages as demonstrated by retroviral overexpression or knockdown of PCSK9 with small interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic activity of PCSK9 was not required for LDLR downregulation since cultured media containing either the catalytic inactive PCSK9 or PCSK9 WT had a similar effect on LDLR in J774. Finally, conditioned media from SMCs affected β-VLDL cholesterol uptake and PCSK9 expression reduced both LDLR and LDL uptake in J774.Taken together our data indicate that PCSK9 secreted by human SMCs is functionally active and capable of reducing LDLR expression in macrophages. A possible direct role for this protein in foam cell formation and atherogenesis is suggested.Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-alpha, LXR-beta, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-alpha, and LXR-beta, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.
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Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid β-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis.
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Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many manifestations of the 'metabolic syndrome'. Most data suggest that the triglycerides serve primarily a storage function with toxicity deriving mainly from long-chain nonesterified fatty acids (NEFA) and their products such as ceramides and diacylglycerols. In the kidney, filtered NEFA carried on albumin can aggravate the chronic tubule damage and inflammatory phenotype that develop during proteinuric states and lipid loading of both glomerular and tubular cells is a common response to renal injury that contributes to progression of nephropathy. NEFA-induced mitochondrial dysfunction is the primary mechanism for energetic failure of proximal tubules during hypoxia/reoxygenation and persistent increases of tubule cell NEFA and triglycerides occur during acute renal failure in vivo in association with downregulation of mitochondrial and peroxisomal enzymes of beta oxidation. In acute renal failure models, peroxisome proliferator-activated receptor alpha ligand treatment can ameliorate the NEFA and triglyceride accumulation and limits tissue injury likely via both direct tubule actions and anti-inflammatory effects. Both acute and chronic kidney disease are associated with systemic manifestations of the metabolic syndrome.
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| [20] |
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
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| [21] |
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