Division of Nephrology, Nanfang Hospital, Southern Medical University and Key Lab for Organ Failure Research, Ministry of Education, Guangzhou, P.R. China.
Kidney Int. 2009 Dec;76(11):1148-60. doi: 10.1038/ki.2009.322. Epub 2009 Sep 2.
The accumulation of plasma advanced oxidation protein products (AOPPs) is prevalent in diverse disorders such as diabetes, metabolic syndromes, and chronic kidney disease. To study whether accumulated AOPPs have an important role in the progression of proteinuria and glomerulosclerosis, we chronically treated normal Sprague-Dawley rats with AOPP-modified rat serum albumin. Podocyte apoptosis was significantly increased coincident with the onset of albuminuria and preceded significant losses of glomerular podocytes. Increasing the amount of AOPPs in the media of conditionally immortalized podocytes rapidly triggered the production of intracellular superoxide by activation of NADPH oxidase and this, in turn, led to an upregulation of p53, Bax, caspase 3 activity, and apoptosis. Chronic inhibition of NADPH oxidase by apocynin prevented podocyte apoptosis, ameliorated podocyte depletion, and decreased albuminuria in AOPP-challenged rats. Our study demonstrates that accumulation of AOPPs promotes NADPH oxidase-dependent podocyte depletion by a p53-Bax apoptotic pathway both in vivo and in vitro.
血浆晚期氧化蛋白产物 (AOPPs) 的积累在多种疾病中很常见，如糖尿病、代谢综合征和慢性肾脏病。为了研究积累的 AOPPs 是否在蛋白尿和肾小球硬化的进展中起重要作用，我们用 AOPP 修饰的大鼠血清白蛋白对正常 Sprague-Dawley 大鼠进行了慢性处理。足细胞凋亡随着蛋白尿的发生而显著增加，并先于肾小球足细胞的明显丢失。在条件永生化的足细胞培养基中增加 AOPPs 的含量，通过激活 NADPH 氧化酶迅速引发细胞内超氧阴离子的产生，进而导致 p53、Bax、caspase 3 活性和细胞凋亡的上调。用 apocynin 慢性抑制 NADPH 氧化酶可防止足细胞凋亡，改善足细胞耗竭，并减少 AOPP 挑战大鼠的蛋白尿。我们的研究表明，AOPPs 的积累通过 p53-Bax 凋亡途径促进 NADPH 氧化酶依赖性足细胞耗竭，无论是在体内还是体外。
