RESUMEN
Secretory phospholipase A2 group IB (sPLA2-IB) and M-type phospholipase A2 receptor (PLA2R) are closely associated with proteinuria in idiopathic membranous nephropathy (IMN). Podocytes constitute an important component of glomerular filtration, and high basal autophagy is indispensable for podocyte function. The current study aimed to analyze the relationship between sPLA2-IB and podocyte autophagy in IMN and determine whether sPLA2-IB mediates abnormal autophagy regulation in podocytes. The serum sPLA2-IB level and podocyte autophagy were detected, and clinical data were collected from IMN patients with different proteinuria levels. Then, the effects of sPLA2-IB on autophagy signaling pathways were evaluated in cultured human podocytes treated with sPLA2-IB, rapamycin, p38 inhibition, and PLA2R-siRNA in vitro. We found that IMN patients with nephrotic-range proteinuria have a significantly higher level of sPLA2-IB and fewer autophagosomes than those with non-nephrotic-range proteinuria. In vitro sPLA2-IB-induced insufficient autophagy in podocytes and promoted podocyte injury via activation of the mTOR/ULK1ser757 signaling pathway. Moreover, inhibition of p38 MAPK evidently abrogated sPLA2-IB-induced autophagy and the activation of mTOR/ULK1ser757 . Additionally, PLA2R silencing demonstrated that sPLA2-IB-induced abnormal autophagy was also PLA2R-dependent. In conclusion, the results revealed that sPLA2-IB downregulated autophagy and contributed to podocyte injury via PLA2R though activation of the p38MAPK/mTOR/ULK1ser757 signaling pathway.
Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Autofagia/genética , Glomerulonefritis Membranosa/sangre , Fosfolipasas A2 Grupo IB/sangre , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Podocitos/metabolismo , Receptores de Fosfolipasa A2/sangre , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adulto , Anciano , Adhesión Celular/genética , Movimiento Celular/genética , Células Cultivadas , Femenino , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/patología , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/sangre , Receptores de Fosfolipasa A2/genética , TransfecciónRESUMEN
BACKGROUND: Serum secretory phospholipase A2 group IB (sPLA2-IB) is involved in the pathological processes of membranous nephropathy (MN). To date, there is no large-scale study validating the usefulness of circulating sPLA2-IB in the follow-up of patients with MN. This study investigated the role of circulating sPLA2-IB in the evaluation of severity of MN. METHODS: A total of 158 patients with primary membranous nephropathy (pMN), 34 with secondary membranous nephropathy (sMN) and 53 healthy controls were enrolled. Histological staging was made for all MN patients. 36 of the pMN patients accepted immunosuppressive therapy and 11 sMN patients who received treatment of primary disease were followed up for 6â¯months. Serum group IB secretory phospholipase A2 (sPLA2-IB), M-type phospholipase A2 receptor antibody (PLA2R-Ab), blood urea nitrogen, creatinine, total protein, albumin, cholesterol, triglyceride and 24-hour urine protein were measured at the time of diagnosis. SPLA2-IB and 24-hour urine protein were measured at the end of follow-up. RESULTS: Circulating sPLA2-IB levels were significantly higher in pMN and sMN patients compared to controls and negatively correlated with TP and albumin, whereas positively correlated with 24-hour urine protein. PLA2-IB was found increased with the severity of proteinuria when divided MN patiens into three groups according to degree of proteinuria. Through the 6-month follow-up, sPLA2-IB and 24â¯h-urine protein levels were found significantly decreased when patients with pMN or sMN reached remission. By ROC analysis, PLA2R-Ab was demonstrated to be most significant in the differential diagnosis of pMN and sMN compared with 24-hour urinary protein and serum sPLA2-IB. CONCLUSION: Despite the limited significance to differentiate pMN from sMN, sPLA2-IB was correlated with the level of proteinuria in MN patients suggesting to be a potential biomarker for monitoring disease severity and therapeutic effects of both pMN and sMN.