Asunto(s)
Cefalea/diagnóstico , Hipertensión Intracraneal/diagnóstico , Angiografía por Resonancia Magnética/métodos , Náusea/complicaciones , Obesidad/complicaciones , Determinación de la Presión Sanguínea , Índice de Masa Corporal , Diagnóstico Diferencial , Femenino , Cefalea/complicaciones , Humanos , Hipertensión Intracraneal/terapia , Náusea/diagnóstico , Obesidad/diagnóstico , Recurrencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Sirolimus (rapamycin), an inhibitor of the mechanistic target of rapamycin (MTOR), was originally proposed as an immunosuppressant to prevent rejection of solid organ transplants. There were expectations that MTOR inhibitors would replace nephrotoxic calcineurin inhibitors (CNIs). Despite its potential advantages, evidence that sirolimus causes de novo or worsening proteinuria is unequivocal. Given the well-recognized proteinuric effect of MTOR inhibitors, we were interested in understanding its role in maintaining the glomerular filtration barrier. To investigate this in vivo, we developed a mouse model with a podocyte selective deletion of the Mtor gene (Mtor pod-KO).
Asunto(s)
Autofagia , Glomérulos Renales/enzimología , Glomérulos Renales/patología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Humanos , Ratones , Ratones Noqueados , Modelos Biológicos , Podocitos/metabolismo , Podocitos/patologíaRESUMEN
Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.