Kelly Katherine J, Wu Pengfei, Patterson Carolyn E, Temm Constance, Dominguez Jesus H
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Am J Physiol Renal Physiol. 2008 May;294(5):F1136-45. doi: 10.1152/ajprenal.00396.2007. Epub 2008 Mar 5.
The early nephropathy in obese, diabetic, dyslipidemic (ZS) rats is characterized by tubular lipid accumulation and pervasive inflammation, two critically interrelated events. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL) in vitro, change their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX-1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of ICAM-1 and focal adhesion kinase, which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor peroxisome proliferator-activated receptor-delta. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti-LOX-1 antibody. The data support the concept that tubular LOX-1 activation driven by lipid oxidants in the preurine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulointerstitial injury of obesity, diabetes, and dyslipidemia.
肥胖、糖尿病、血脂异常（ZS）大鼠的早期肾病特征为肾小管脂质蓄积和广泛炎症，这两个事件密切相关。我们现在检验了这样一个假设：ZS肥胖糖尿病大鼠体内的近端肾小管以及体外暴露于氧化型低密度脂蛋白（oxLDL）的近端肾小管细胞（NRK52E）会将其正常静止的上皮表型转变为促炎表型。肥胖糖尿病大鼠的尿液中含有更多脂质过氧化物，且内化氧化脂质的膜受体凝集素样氧化低密度脂蛋白受体1（LOX-1）被转运至管腔部位。分别参与白细胞迁移和上皮去分化的细胞间黏附分子1（ICAM-1）和黏着斑激酶水平在肾小管中也上调。暴露于oxLDL的NRK52E细胞表现出类似变化，同时抗炎转录因子过氧化物酶体增殖物激活受体δ（PPAR-δ）受到抑制。此外，oxLDL损害上皮屏障功能。这些改变可被抗LOX-1抗体阻止。数据支持这样的概念，即尿液前液中脂质氧化剂驱动的肾小管LOX-1激活在炎症变化中起关键作用。我们认为管腔脂质氧化剂和异常的肾小管通透性可能部分导致肥胖、糖尿病和血脂异常患者的肾小管间质损伤。
