RESUMEN
Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses≥0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.
Asunto(s)
Ácido Kaínico/análogos & derivados , Toxinas Marinas/toxicidad , Fármacos Neuromusculares Despolarizantes/toxicidad , Unión Neuromuscular/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Ácido Kaínico/farmacocinética , Ácido Kaínico/toxicidad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Toxinas Marinas/farmacocinética , Ratones Endogámicos , Microscopía Electrónica de Transmisión , Dilatación Mitocondrial/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Fármacos Neuromusculares Despolarizantes/farmacocinética , Unión Neuromuscular/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Ácido Kaínico/genética , Receptores de Ácido Kaínico/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vacuolas/patología , Vacuolas/ultraestructura , Receptor de Ácido Kaínico GluK2RESUMEN
Mitochondrial biogenesis may be an adaptive response necessary for meeting the increased metabolic and energy demands during organ recovery after acute injury, and renal mitochondrial dysfunction has been implicated in the pathogenesis of AKI. We proposed that stimulation of mitochondrial biogenesis 24 hours after ischemia/reperfusion (I/R)-induced AKI, when renal dysfunction is maximal, would accelerate recovery of mitochondrial and renal function in mice. We recently showed that formoterol, a potent, highly specific, and long-acting ß2-adrenergic agonist, induces renal mitochondrial biogenesis in naive mice. Animals were subjected to sham or I/R-induced AKI, followed by once-daily intraperitoneal injection with vehicle or formoterol beginning 24 hours after surgery and continuing through 144 hours after surgery. Treatment with formoterol restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Taken together, these results provide proof of principle that a novel drug therapy to treat AKI, and potentially other acute organ failures, works by restoring mitochondrial function and accelerating the recovery of renal function after injury has occurred.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Etanolaminas/farmacología , Riñón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/fisiopatología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fumarato de Formoterol , Riñón/fisiología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatologíaRESUMEN
Kidney ischemia-reperfusion (I/R) injury elicits cellular injury in the proximal tubule, and mitochondrial dysfunction is a pathological consequence of I/R. Promoting mitochondrial biogenesis (MB) as a repair mechanism after injury may offer a unique strategy to restore both mitochondrial and organ function. Rats subjected to bilateral renal pedicle ligation for 22 min were treated once daily with the SIRT1 activator SRT1720 (5mg/kg) starting 24h after reperfusion until 72h-144 h. SIRT1 expression was elevated in the renal cortex of rats after I/R+vehicle treatment (IRV), but was associated with less nuclear localization. SIRT1 expression was even further augmented and nuclear localization was restored in the kidneys of rats after I/R+SRT1720 treatment (IRS). PGC-1α was elevated at 72 h-144 h in IRV and IRS kidneys; however, SRT1720 treatment induced deacetylation of PGC-1α, a marker of activation. Mitochondrial proteins ATP synthase ß, COX I, and NDUFB8, as well as mitochondrial respiration, were diminished 24h-144 h in IRV rats, but were partially or fully restored in IRS rats. Urinary kidney injury molecule-1 (KIM-1) was persistently elevated in both IRV and IRS rats; however, KIM-1 tissue expression was attenuated in IRS rats. Additionally, sustained loss of Na(+),K(+)-ATPase expression and basolateral localization and elevated vimentin in IRV rats was normalized in IRS rats, suggesting restoration of a differentiated, polarized tubule epithelium. The results suggest that SRT1720 treatment expedited recovery of mitochondrial protein expression and function by enhancing MB, which was associated with faster proximal tubule repair. Targeting MB may offer unique therapeutic strategy following ischemic injury.
Asunto(s)
Homeostasis/fisiología , Túbulos Renales/metabolismo , Mitocondrias/metabolismo , Daño por Reperfusión/metabolismo , Sirtuina 1/biosíntesis , Factores de Transcripción/biosíntesis , Animales , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Homeostasis/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patologíaRESUMEN
While mitochondrial dysfunction is a pathological process that occurs after acute kidney injury (AKI), the state of mitochondrial homeostasis during the injury and recovery phases of AKI remains unclear. We examined markers of mitochondrial homeostasis in two nonlethal rodent AKI models. Myoglobinuric AKI was induced by glycerol injection into rats, and mice were subjected to ischemic AKI. Animals in both models had elevated serum creatinine, indicative of renal dysfunction, 24 h after injury which partially recovered over 144 h postinjury. Markers of proximal tubule function/injury, including neutrophil gelatinase-associated lipocalin and urine glucose, did not recover during this same period. The persistent pathological state was confirmed by sustained caspase 3 cleavage and evidence of tubule dilation and brush-border damage. Respiratory proteins NDUFB8, ATP synthase ß, cytochrome c oxidase subunit I (COX I), and COX IV were decreased in both injury models and did not recover by 144 h. Immunohistochemical analysis confirmed that COX IV protein was progressively lost in proximal tubules of the kidney cortex after ischemia-reperfusion (I/R). Expression of mitochondrial fission protein Drp1 was elevated after injury in both models, whereas the fusion protein Mfn2 was elevated after glycerol injury but decreased after I/R AKI. LC3-I/II expression revealed that autophagy increased in both injury models at the later time points. Markers of mitochondrial biogenesis, such as PGC-1α and PRC, were elevated in both models. These findings reveal that there is persistent disruption of mitochondrial homeostasis and sustained tubular damage after AKI, even in the presence of mitochondrial recovery signals and improved glomerular filtration.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Homeostasis , Mitocondrias/fisiología , Lesión Renal Aguda/etiología , Animales , Autofagia , Isquemia , Riñón/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Rabdomiólisis/complicacionesRESUMEN
In the periphery, exercise induces interleukin (IL)-6 to downregulate tumor necrosis factor (TNF), elevate interleukin-1 receptor antagonist (IL-1RA), decreasing inflammation. Exercise also offers neuroprotection and facilitates brain repair. IL-6 production in the hippocampus following exercise suggests the potential of a similar protective role as in the periphery to down-regulate TNFα and inflammation. Using a chemical-induced model of hippocampal dentate granule cell death (trimethyltin, TMT 2.4 mg/kg, ip) dependent upon TNF receptor signaling, we demonstrate neuroprotection in mice with 2 weeks access to running wheel. Exercise attenuated neuronal death and diminished elevations in TNFα, TNF receptor 1, myeloid differentiation primary response gene (MyD) 88, transforming growth factor ß, chemokine (C-C motif) ligand 2 (CCL2), and CCL3. Elevated mRNA levels for IL-1α, IL-1RA, occurred with injury and protection. mRNA and protein levels of IL-6 and neuronal expression of IL-6 receptor α, were elevated with injury and protection. Microarray pathway analysis supported an up-regulation of TNFα cell death signaling pathways with TMT and inhibition by exercise. IL-6 pathway recruitment occurred in both conditions. IL-6 downstream signal events differed in the level of STAT3 activation. Exercise did not increase mRNA levels of brain derived neurotrophic factor, nerve growth factor, or glial derived neurotrophic factor. In IL-6 deficient mice, exercise did not attenuate TMT-induced tremor and a diminished level of neuroprotection was observed. These data suggest a contributory role for IL-6 induced by exercise for neuroprotection in the CNS similar to that seen in the periphery.
Asunto(s)
Hipocampo/efectos de los fármacos , Interleucina-6/fisiología , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Condicionamiento Físico Animal/fisiología , Receptores del Factor de Necrosis Tumoral/efectos de los fármacos , Compuestos de Trimetilestaño/toxicidad , Animales , Quimiocinas/biosíntesis , Quimiocinas/genética , Epilepsia Tónico-Clónica/inducido químicamente , Hipocampo/metabolismo , Hipocampo/patología , Interleucina-6/biosíntesis , Interleucina-6/deficiencia , Interleucina-6/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Neurológicos , Factor 88 de Diferenciación Mieloide/biosíntesis , Factor 88 de Diferenciación Mieloide/genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Neuronas/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Quimera por Radiación , Distribución Aleatoria , Receptores del Factor de Necrosis Tumoral/biosíntesis , Receptores del Factor de Necrosis Tumoral/fisiología , Organismos Libres de Patógenos Específicos , Temblor/inducido químicamente , Factor de Necrosis Tumoral alfa/fisiología , Regulación hacia ArribaRESUMEN
Mitochondrial biogenesis occurs under basal conditions and is an adaptive response initiated by cells to maintain energetic demands and metabolic homeostasis after injuries targeting mitochondrial function. Identifying pharmacological agents that stimulate mitochondrial biogenesis is a critical step in the development of new therapeutics for the treatment of these injuries and to test the hypothesis that these agents will expedite recovery of cell and organ function after acute organ injuries. In this study, we examined the effects of N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide (SRT1720) on mitochondrial biogenesis and function in primary cultures of renal proximal tubule cells (RPTCs). We also tested the ability of this compound to restore mitochondrial functions after oxidant-induced RPTC injury. SRT1720 (3-10 microM) induced mitochondrial biogenesis in RPTCs within 24 h as determined by elevations in mitochondrial DNA copy number, increased expression of the mitochondrial proteins NADH dehydrogenase 1beta subcomplex subunit 8 (NDUFB8) and ATP synthase beta, and elevated mitochondrial respiration rates and ATP levels. Induction of mitochondrial biogenesis depended on mammalian sirtuin 1 (SIRT1) deacetylase activity, correlated with deacetylated nuclear peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, and occurred in the absence of AMP-dependent kinase (AMPK) activation. Finally, SRT1720 treatment accelerated recovery of mitochondrial functions after acute oxidant injury. This study demonstrates that SRT1720 can induce mitochondrial biogenesis through SIRT1 activity and deacetylated PGC-1alpha, but not AMPK, in RPTCs within 24 h after oxidant injury. The results support further study of mitochondrial biogenesis as a repair process and a pharmacological target in acute organ injuries and disorders plagued by mitochondrial impairment.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Adenosina Trifosfato/análisis , Animales , Células Cultivadas , ADN Mitocondrial/análisis , Femenino , Immunoblotting , Inmunoprecipitación , Túbulos Renales Proximales/química , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/fisiopatología , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Consumo de Oxígeno/efectos de los fármacos , PPAR alfa/metabolismo , Reacción en Cadena de la Polimerasa , ConejosRESUMEN
Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisome-proliferator-activated-receptor-gamma-coactivator-1alpha (PGC-1alpha). The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. Reverse transcription-polymerase chain reaction analysis confirmed the presence of 5-HT2A, 5-HT2B, and 5-HT2C receptor mRNA in RPTC. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 3-10 microM) increased PGC-1alpha levels, expression of mitochondrial proteins ATP synthase beta and NADH dehydrogenase (ubiquinone) 1beta subcomplex 8 (NDUFB8), MitoTracker Red staining intensity, cellular respiration, and ATP levels through a 5-HT receptor and PGC-1alpha-dependent pathway. Similar effects were observed with the 5-HT2 agonist m-chlorophenylpiperazine and were blocked by the 5-HT2 antagonist 8-[3-(4-fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (AMI-193). In addition, DOI accelerated the recovery of mitochondrial function after oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor-mediated mitochondrial biogenesis, and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury.
Asunto(s)
Anfetaminas/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Factores de Transcripción/genética , Animales , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Proteínas de Choque Térmico , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Mitocondrias Musculares , Consumo de Oxígeno , Piperazinas/farmacología , Regiones Promotoras Genéticas , Conejos , Antagonistas de la Serotonina/farmacología , Compuestos de Espiro/farmacologíaRESUMEN
Localized tumor necrosis factor-alpha (TNFalpha) elevation has diverse effects in brain injury often attributed to signaling via TNFp55 or TNFp75 receptors. Both dentate granule cells and CA pyramidal cells express TNF receptors (TNFR) at low levels in a punctate pattern. Using a model to induce selective death of dentate granule cells (trimethyltin; 2 mg/kg, i.p.), neuronal apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ end labeling, active caspase 3 (AC3)] was accompanied by amoeboid microglia and elevated TNFalpha mRNA levels. TNFp55R (55 kDa type-1 TNFR) and TNFp75R (75 kDa type-2 TNFR) immunoreactivity in AC3(+) neurons displayed a pattern suggestive of receptor internalization and a temporal sequence of expression of TNFp55R followed by TNFp75R associated with the progression of apoptosis. A distinct ramified microglia response occurred around CA1 neurons and healthy dentate neurons that displayed an increase in the normal punctate pattern of TNFRs. Neuronal damage was decreased with i.c.v. injection of TNFalpha antibody and in TNFp55R-/-p75R-/- mice that showed higher constitutive mRNA levels for interleukin (IL-1alpha), macrophage inflammatory protein 1-alpha (MIP-1alpha), TNFalpha, transforming growth factor beta1, Fas, and TNFRSF6-assoicated via death domain (FADD). TNFp75R-/- mice showed exacerbated injury and elevated mRNA levels for IL-1alpha, MIP-1alpha, and TNFalpha. In TNFp55R-/- mice, constitutive mRNA levels for TNFalpha, IL-6, caspase 8, FADD, and Fas-associated phosphatase were higher; IL-1alpha, MIP-1alpha, and transforming growth factor beta1 lower. The mice displayed exacerbated neuronal death, delayed microglia response, increased FADD and TNFp75R mRNA levels, and co-expression of TNFp75R in AC3(+) neurons. The data demonstrate TNFR-mediated apoptotic death of dentate granule neurons utilizing both TNFRs and suggest a TNFp75R-mediated apoptosis in the absence of normal TNFp55R activity.
Asunto(s)
Apoptosis/inmunología , Giro Dentado/metabolismo , Degeneración Nerviosa/metabolismo , Neuronas/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Citocinas/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Giro Dentado/inmunología , Giro Dentado/patología , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Proteína de Dominio de Muerte Asociada a Fas/efectos de los fármacos , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/inmunología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/inmunología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neurotoxinas/toxicidad , Receptores de Factor de Crecimiento Nervioso/efectos de los fármacos , Receptores de Factor de Crecimiento Nervioso/genética , Receptores del Factor de Necrosis Tumoral/efectos de los fármacos , Receptores del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/efectos de los fármacos , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Compuestos de Trimetilestaño/toxicidadRESUMEN
Alterations in inflammatory process, neuronal death, and glia response have been observed under manipulation of interleukin-1 (IL-1) and subsequent signaling through the type 1 IL-1 receptor (IL-1R1). To investigate the influence of IL-1R1 activation in the pathophysiology of a chemical-induced injury to the murine hippocampus, we examined the level and pattern of neuronal death and neuroinflammation in male weanling mice exposed to trimethyltin hydroxide (2.0 mg TMT/kg, i.p.). Dentate granule cell death occurred at 6 h post-TMT as detected by active caspase 3 immunostaining and presence of lectin positive microglia. The severity of neuronal death and microglia response increased by 12-24 h with elevations in mRNA levels for TNFalpha and IL-1alpha. In IL-1R1 null (IL-1R1-/-) mice, the pattern and severity of neuronal death at 24 or 72 h post-TMT was similar as compared to wildtype (WT) mice. In both groups, mRNA levels for TNFalpha and MIP-1alpha were elevated, no significant change was seen in either IL-1alpha or IL-1beta, and the early activation of microglia, including their ability to progress to a phagocytic phenotype, was maintained. Compared to WT mice, IL-1R1-/- mice displayed a limited glial fibrillary acidic protein (GFAP) astrocytic response, as well as a preferential induction in mRNA levels of Fas signaling components. Cumulatively, these results indicate that IL-1R1 activation is not necessary for TMT-induced death of dentate granule neurons or local activation of microglia; however, IL-1R1 signaling is involved in mediating the structural response of astrocytes to injury and may regulate apoptotic mechanisms via Fas signaling components.
Asunto(s)
Giro Dentado/citología , Microglía/fisiología , Neuronas/fisiología , Receptores de Interleucina-1/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Lectinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , Neuronas/efectos de los fármacos , Distribución Aleatoria , Receptores de Interleucina-1/deficiencia , Factores de Tiempo , Compuestos de Trimetilestaño/farmacología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Huntington's disease (HD) is a hereditary neurodegenerative disease that leads to striatal degeneration and a severe movement disorder. We used a transgenic mouse model of HD (the R6/2 line with approximately 150 glutamine repeats) to test a new therapy for this disease. We treated HD mice with metformin, a widely used anti-diabetes drug, in the drinking water (0, 2 or 5mg/ml) starting at 5 weeks of age. Metformin treatment significantly prolonged the survival time of male HD mice at the 2mg/ml dose (20.1% increase in lifespan) without affecting fasting blood glucose levels. This dose of metformin also decreased hind limb clasping time in 11-week-old mice. The higher dose did not prolong survival, and neither dose of metformin was effective in female HD mice. Collectively, our results suggest that metformin may be worth further investigation in additional HD models.
Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Proteínas Quinasas Activadas por AMP , Factores de Edad , Animales , Conducta Animal , Glucemia/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Femenino , Glutamina/genética , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores Sexuales , Repeticiones de Trinucleótidos/genéticaRESUMEN
The kidneys compose approximately 0.5% of the body mass but consume about 10% of the oxygen in cellular respiration. This discordance is due to the high energy demands on the kidney for reabsorption of filtered blood components and makes the kidney sensitive to mitochondrial stress, the primary source of cellular ATP. Regardless of the etiology, acute kidney injury (AKI) almost always involves aspects of mitochondrial dysfunction. Recent evidence from experimental models suggests that preserving mitochondrial function or promoting mitochondrial repair rescues renal function during AKI. In this review we discuss the effect of AKI on disruption of mitochondrial homeostasis, and how the dynamic processes of mitochondrial biogenesis, fission/fusion, and mitophagy influence renal injury and recovery.