Klahr S, Morrissey J J
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Kidney Int Suppl. 1997 Dec;63:S111-4.
Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney diseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibrosis include monocyte/macrophage infiltration, the synthesis of profibrotic cytokines such as transforming growth factor beta 1 (TGF-beta 1), interstitial myofibroblast proliferation, and clusterin expression. These processes are ameliorated by angiotensin converting enzyme (ACE) inhibition. Blockade of the angiotensin II receptor (AT-1) impaired fibroblast proliferation, consequent differentiation into myofibroblasts, and the synthesis of TGF-beta 1, but did not prevent monocyte infiltration. TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression. The nuclear factor-kappa B (NF-kappa B) family of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 receptor blockade each differentially attenuated NF-kappa B isotype activation. The changes in NF-kappa B isotype may account for the variation seen in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to prevent renal disease progression, one must be aware of the impact of transcription factors on the injured kidney and the consequent changes in cell infiltration, proliferation and differentiation.
许多与肾脏疾病相关的病理生理事件是由血管紧张素II驱动的。无论病因如何，许多肾脏疾病都会导致肾小管间质炎症、纤维化和肾功能丧失。肾小管间质纤维化过程的促成因素包括单核细胞/巨噬细胞浸润、促纤维化细胞因子如转化生长因子β1（TGF-β1）的合成、间质肌成纤维细胞增殖和簇集素表达。这些过程通过抑制血管紧张素转换酶（ACE）得以改善。阻断血管紧张素II受体（AT-1）可损害成纤维细胞增殖、随后分化为肌成纤维细胞以及TGF-β1的合成，但不能阻止单核细胞浸润。TGF-β1合成或成纤维细胞增殖，但阻止了成纤维细胞分化为肌成纤维细胞并阻断了簇集素表达。转录因子核因子-κB（NF-κB）家族调节参与炎症、增殖和分化的基因。ACE抑制、AT-1和AT-2受体阻断分别不同程度地减弱了NF-κB同型激活。NF-κB同型的变化可能解释了血管紧张素II形成或作用对纤维化过程的药理作用中所观察到的差异。在考虑预防肾脏疾病进展的治疗选择时，必须意识到转录因子对受损肾脏的影响以及随之而来的细胞浸润、增殖和分化的变化。
