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环加氧酶可将花生四烯酸代谢成一系列具有活性的脂肪酸即前列腺素。其中，COX-1为原生型加氧酶，在全身多处存在，对肾脏、胃肠道固有功能起重要作用。而COX-2则为诱生型，主要在肾脏的致密斑、髓袢升支及髓质间质部分，参与水钠代谢、肾素调节等。当肾脏组织损伤时，COX-2表达明显上升，后者可能参与了生长因子、细胞因子等释放。选择性COX-2抑制可以主要抑制由炎症等引导的结果，对肾脏、胃肠道等由COX-1所诱导的固有功能影响较少。应用COX-2抑制可以减少尿蛋白。近年来有实验证实在5/6肾大部分切除的动物模型中，使用COX-2抑制剂可以明显减轻肾小球硬化、小管间质纤维化，对TGF-β表达也明显减轻。也有实验证实，COX-2抑制剂对糖尿病肾病、阿霉素肾病、单侧输尿管结扎所致的梗阻性肾病等病变有好处。上述模型中COX-2抑制所致的效应，可能机制包括：改善肾脏血流动力学，减少TGF-β的生成，改善胰岛素代谢，减少多肽趋化因子（MCP-1)生成等。COX-2在各型临床肾病中应用尚缺乏足够证据。
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（四）PPAR-γ激动剂
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PPAR为核激素受体超家族转录因子，能调节许多细胞代谢过程包括脂肪代谢、糖代谢、细胞周期、细胞分化、炎症和细胞外基质重塑等。肾脏组织中可检测出多种PPAR异构体。肾小球系膜细胞、髓质集合小管等都存在PPAR-γ。实验证实，应用PPAR-γ激动剂如罗格力酮、曲格力酮等，不仅可以改善异常代谢，还可以减轻某些肾脏病病变程度。糖尿病肾病、单侧输尿管结扎所致的梗阻性肾病等，应用罗格力酮可以减轻小管间质纤维化程度，降低TGF-β、MCP-1等表达。还观察到在由内皮素阻滞剂所致糖尿病肾病进展的保护机制中，PPAR-γ下游的抑制因子脂肪酸转运蛋白参与作用。
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【思考题】
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1．试述ACEI肾功能保护作用的非降压、非血流动力学机制。
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2．根据目前研究状况，在肾脏疾病慢性进展理论方面还可以进行哪些研究？
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参考文献
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[1] 陈灏珠主编．慢性肾功能衰竭．实用内科学．第12版．北京：人民卫生出版社，2005，2078.
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[2] Couser WG, Nangku M. Cellular and molecular biology of membranous nephropathy. J Nephrol, 2006, 19(6)
:699-705.
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[3] Nagase M, Yoshida S, Shibata S et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol, 2006, 17(12)
:3438-46.
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[4] Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med, 2004, 116(4)
:263-72.
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[5] Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest, 2003, 112(12)
:1776-84.
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[6] Nakanishi T, Ishigami Y, Otaki Y, et al. Impairment of vascular responses to reactive hyperemia and nitric oxide in chronic renal failure. Nephron, 2002, 92(3)
:529-35.
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[7] Suzuki T, Kimura M, Asano M, et al. Role of atrophic tubules in development of interstitial fibrosis in microembolism-induced renal failure in rat. Am J Pathol, 2001, 158(1)
:75-85.
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[8] De Muro P, Faedda R, Fresu P, et al. Urinary transforming growth factor-beta1 in various types of nephropathy. Pharmacol Res, 2004, 49(3)
:293-8.
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[9] Lu F, Li P, Zheng F, et al. Serum insulin-like growth factor 1 level and nutritional assessment in nondialytic patients with chronic renal failure. Kidney Blood Press Res, 2002, 25(2)
:116-9.
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[10] Richmond EJ, Uzri A, Rogol AD. The insulin-like growth factor system in kidney diseases. Nephron, 2001, 89(1)
:5-9.
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[11] Ambrosch A, Muller R, Freytag C, et al. Small-sized low-density lipoproteins of subclass B from patients with end-stage renal disease effectively augment tumor necrosis factor-alpha-induced adhesive properties in human endothelial cells. Am J Kidney Dis, 2002, 39(5)
:972-84.
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[12] Kobayashi E, Sasamura H, Mifune M, et al. Hepatocyte growth factor regulates proteoglycan synthesis in interstitial fibroblasts. Kidney Int, 2003, 64(4)
:1179-88.
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（陈伊伦）
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内科学新进展 第二节 延缓慢性肾功能衰竭进展策略
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摘 要 任何病因的肾脏疾病都会导致肾单位丢失，并产生蛋白尿、高血压、肾功能不全的临床综合征。RAS阻断可作为延缓慢性肾脏病（CKD）进展的基础治疗。目标血压＜130/80mm Hg; 蛋白尿＜0.5g/d应作为一个独立的治疗目标；尽管有争议，低蛋白饮食〔0.6g/(kg·d）〕对于CKD患者是合适的。高脂血症会加重CKD进展，治疗高脂血症可能改善肾功能；戒烟与血糖控制有助于延缓CKD进展。这些干预措施简单有效，将有效延缓肾功能衰竭，并减少终末期肾功能衰竭的发生率。
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Abstract Kidney disease of any cause all results in substantial loss of nephrons, characterised by hypertension, proteinuria and a progressive decline in renal function, Therefore, the use of renin-angiotensin-system（RAS）antagonists should be regarded as fundamental therapy for slowing the progression of CKD. Hypertension should be treated aggressively to achieve a blood pressure target of ＜130/80mmHg. Reduction of proteinuria to ＜0.5g/day should be regarded as an independent therapeutic goal. Although inconclusive, there is some evidence to support moderate dietary protein restriction to 0.6g/(kg·d）in CKD patients. Hyperlipidaemia may contribute to CKD progression and should be treated to reduce cardiovascular risk and potentially improve renal protection. Smoking cessation should be encouraged and, where necessary, assisted. Among diabetic patients tight glycaemic control should be achieved（glycosylated haemoglobin ＜7%). These interventions are simple and relatively inexpensive. If applied to all patients with CKD, they will result in substantial slowing of renal function deteriorations in many patients and thereby reduce the incidence of end-stage renal disease and require renal replacement therapy.
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