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1.
J Biol Chem ; 295(47): 16002-16012, 2020 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-32907879

RESUMEN

Podocyte injury is a critical step toward the progression of renal disease and is often associated with a loss of slit diaphragm proteins, including Podocin. Although there is a possibility that the extracellular domain of these slit diaphragm proteins can be a target for a pathological proteolysis, the precise mechanism driving the phenomenon remains unknown. Here we show that Matriptase, a membrane-anchored protein, was activated at podocytes in CKD patients and mice, whereas Matriptase inhibitors slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), because conditional depletion of HAI-1 in podocytes accelerated podocyte injury in mouse model. Matriptase was capable of cleaving Podocin, but such a reaction was blocked by either HAI-1 or dominant-negative Matriptase. Furthermore, the N terminus of Podocin, as a consequence of Matriptase cleavage of Podocin, translocated to nucleoli, suggesting that the N terminus of Podocin might be involved in the process of podocyte injury. Given these observations, we propose that the proteolytic cleavage of Podocin by Matriptase could potentially cause podocyte injury and that targeting Matriptase could be a novel therapeutic strategy for CKD patients.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Podocitos/metabolismo , Proteolisis , Insuficiencia Renal Crónica/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Podocitos/patología , Dominios Proteicos , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Serina Endopeptidasas/genética
2.
Biochem Biophys Res Commun ; 454(4): 531-6, 2014 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-25450688

RESUMEN

In human diabetic nephropathy, glomerular injury was found to comprise lipid droplets, suggesting that abnormal lipid metabolism might take place in the development of diabetic glomerular injury. However, its precise mechanism remains unclear. Fatty acid binding protein (FABP) is currently considered as a key molecule for lipid metabolism. Since diabetic eNOS knockout (KO) mouse is considered to be a good model for human diabetic nephropathy, we here investigated whether FABP could mediate glomerular injury in this model. We found that glomerular injuries were associated with inflammatory processes, such as macrophage infiltration and MCP-1 induction. Microarray assay with isolated glomeruli revealed that among 10 isoforms in FABP family, FABP3 mRNA was most highly expressed in diabetic eNOSKO mice compared to non-diabetic eNOSKO mice. FABP3 protein was found to be located in the mesangial cells. Overexpression of FABP3 resulted in a greater response to palmitate, a satulated FA, to induce MCP-1 in the rat mesangial cells. In turn, the heart, a major organ for FABP3 protein in normal condition, failed to alter its expression level under diabetic condition in either wild type or eNOSKO mice. In conclusion, FABP3 is induced in the mesangial cells and likely a mediator to induce MCP-1 in the diabetic nephropathy.


Asunto(s)
Nefropatías Diabéticas/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Animales , Quimiocina CCL2/metabolismo , Proteína 3 de Unión a Ácidos Grasos , Proteínas de Unión a Ácidos Grasos/genética , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
3.
Sci Rep ; 5: 18575, 2015 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-26677804

RESUMEN

Differentiated podocytes, a type of renal glomerular cells, require substantial levels of energy to maintain glomerular physiology. Mitochondria and glycolysis are two major producers of ATP, but the precise roles of each in podocytes remain unknown. This study evaluated the roles of mitochondria and glycolysis in differentiated and differentiating podocytes. Mitochondria in differentiated podocytes are located in the central part of cell body while blocking mitochondria had minor effects on cell shape and migratory ability. In contrast, blocking glycolysis significantly reduced the formation of lamellipodia, a cortical area of these cells, decreased the cell migratory ability and induced the apoptosis. Consistently, the local ATP production in lamellipodia was predominantly regulated by glycolysis. In turn, synaptopodin expression was ameliorated by blocking either mitochondrial respiration or glycolysis. Similar to differentiated podocytes, the differentiating podocytes utilized the glycolysis for regulating apoptosis and lamellipodia formation while synaptopodin expression was likely involved in both mitochondrial OXPHOS and glycolysis. Finally, adult mouse podocytes have most of mitochondria predominantly in the center of the cytosol whereas phosphofructokinase, a rate limiting enzyme for glycolysis, was expressed in foot processes. These data suggest that mitochondria and glycolysis play parallel but distinct roles in differentiated and differentiating podocytes.


Asunto(s)
Adenosina Trifosfato/metabolismo , Mitocondrias/metabolismo , Citoesqueleto de Actina/efectos de los fármacos , Animales , Antimicina A/análogos & derivados , Antimicina A/farmacología , Apoptosis/efectos de los fármacos , Diferenciación Celular , Línea Celular , Movimiento Celular/efectos de los fármacos , Citoplasma/metabolismo , Desoxiglucosa/farmacología , Glucólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Fosforilación Oxidativa/efectos de los fármacos , Fosfofructoquinasas/antagonistas & inhibidores , Fosfofructoquinasas/genética , Fosfofructoquinasas/metabolismo , Podocitos/citología , Podocitos/metabolismo , Seudópodos/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo
4.
Free Radic Biol Med ; 87: 181-92, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26119782

RESUMEN

The contribution of endothelial nitric oxide synthase (eNOS) to podocyte integrity remains unclear. This study therefore examined podocytes and mitochondrial abnormalities in eNOS deficient mice. Absence of eNOS caused glomerular hypertrophy, along with occasional glomerular sclerosis and mesangiolysis. While many glomeruli did not have such advanced lesions, ultrastructural analysis showed cellular hypertrophy, vacuolization, lysosomal enlargement, and microvillus formation in podocytes of eNOS knockout (KO) mice. Increased oxidative stress was associated with mitochondrial abnormalities, including an increase in number, coupled with a reduction in size, of mitochondria in podocytes of eNOS-KO mice. While the levels of expression of several mitochondrial proteins were not altered, the d-17 mutation in mitochondrial DNA was significantly associated with the eNOS deficiency. Renal ATP level in the renal cortex and mitochondrial respiration in the primary podocytes were significantly lower in eNOS-KO mice, suggesting that renal mitochondria may be functionally impaired. Podocytes cultured with endothelial conditioned medium lacking NO consistently showed a greater degree of mitochondrial fragmentation and an increase in mitochondrial oxidative stress, with these mitochondrial alterations rescued by an NO donor. In conclusion, eNOS may be necessary to maintain podocyte integrity, especially mitochondrial function.


Asunto(s)
Enfermedades Renales/genética , Mitocondrias/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Podocitos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Humanos , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratones , Ratones Noqueados , Mitocondrias/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Estrés Oxidativo/genética , Podocitos/patología
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