Aoudjit Lamine, Potapov Anna, Takano Tomoko
McGill University Health Centre, Montreal, Quebec, Canada.
Am J Physiol Renal Physiol. 2006 Jun;290(6):F1534-42. doi: 10.1152/ajprenal.00267.2005. Epub 2006 Jan 5.
Visceral glomerular epithelial cells (GEC) are crucial for glomerular permselectivity and structural integrity in the kidney. The current study addressed the role of cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 in GEC survival. We generated a subclone of cultured rat GEC, which overexpress COX-2 in an inducible manner. When COX-2 was induced, GEC survived better in serum-deprived conditions. Induction of COX-2 was correlated with increased PGE2 generation, increased activation of extracellular signal-regulated kinase, decreased apoptosis, and increased cell proliferation. Rat GEC abundantly expressed the EP4 isoform of PGE2 receptor. Induction of COX-2 and addition of exogenous PGE2 both lead to decreased serum deprivation-induced apoptosis, which was accompanied by activation of the survival kinase Akt. Anti-apoptotic effect of COX-2 induction was reversed by the specific inhibitor of the EP4 receptor, L-161982. PGE2 also inhibited puromycin aminonucleoside-induced GEC apoptosis in vitro. Acute puromycin aminonucleoside nephrosis (PAN) is a rat model of GEC injury and proteinuria. In rats with PAN, glomerular apoptosis, quantified as caspase-3 activity, as well as urinary protein excretion were significantly increased, compared with control rats. Administration of L-161982 in rats with PAN further exacerbated caspase-3 activation and proteinuria. Thus COX-2 and its product PGE2 may have anti-apoptotic/protective effect on GEC via the EP4 receptor of PGE2.
内脏肾小球上皮细胞（GEC）对于肾脏的肾小球滤过选择性和结构完整性至关重要。本研究探讨了环氧化酶（COX）-2及其产物前列腺素（PG）E2在GEC存活中的作用。我们构建了一个培养的大鼠GEC亚克隆，其以可诱导的方式过表达COX-2。当诱导COX-2时，GEC在血清剥夺条件下存活得更好。COX-2的诱导与PGE2生成增加、细胞外信号调节激酶的激活增加、细胞凋亡减少以及细胞增殖增加相关。大鼠GEC大量表达PGE2受体的EP4亚型。COX-2的诱导和外源性PGE2的添加均导致血清剥夺诱导的细胞凋亡减少，这伴随着存活激酶Akt的激活。EP4受体的特异性抑制剂L-161982可逆转COX-2诱导的抗凋亡作用。PGE2在体外也抑制嘌呤霉素氨基核苷诱导的GEC凋亡。急性嘌呤霉素氨基核苷肾病（PAN）是一种GEC损伤和蛋白尿的大鼠模型。与对照大鼠相比，PAN大鼠的肾小球凋亡（以caspase-3活性定量）以及尿蛋白排泄显著增加。给PAN大鼠施用L-161982进一步加剧了caspase-3的激活和蛋白尿。因此，COX-2及其产物PGE2可能通过PGE2的EP4受体对GEC具有抗凋亡/保护作用。
