Div. of Kidney Diseases and Hypertension, Rhode Island Hospital, Providence, RI 02903, USA.
Am J Physiol Renal Physiol. 2010 May;298(5):F1178-87. doi: 10.1152/ajprenal.00532.2009. Epub 2010 Mar 3.
Aldosterone (Aldo) can be a profibrotic factor in cardiovascular and renal tissues. This study tests the hypothesis that prolonged Aldo exposure is able to directly induce fibrotic changes in the kidney of a normal nonhypertensive animal. Immortalized rat proximal tubule cells (IRPTC) containing 11β-hydroxysteroid dehydrogenase (11β-HSD1) but no mineralocorticoid receptors (MR) and mouse inner medullary collecting duct cells (IMCD) containing 11β-HSD2 and MR were examined. IRPTC exposed to Aldo or corticosterone (10 nM) for 48 h demonstrated no change in collagen production as assessed by Sirius red staining. In contrast, IMCD treated with Aldo exhibited a marked increase in the expression of collagen, fibronectin, and connective tissue growth factor (CTGF), whereas corticosterone alone had no effect. The Aldo-induced overexperession of collagen, fibronectin, and CTGF was substantially attenuated by the MR antagonist RU-318 and by the 11β-HSD end product 11-dehydrocorticosterone, but not by the glucocorticoid receptor antagonist RU-486. In vivo, early fibrotic changes with elevated collagen, fibronectin, and CTGF expression were observed in kidneys isolated from normotensive adrenalectomized mice receiving a continuous infusion of Aldo (8 μg·kg(-1)·day(-1)) for 1 wk. These changes were not present in corticosterone-treated mice. Aldo-induced changes were attenuated in adrenally intact mice and in mice treated with RU-318 or 11-dehydrocorticosterone. Thus, extended Aldo exposure produces fibrotic changes in cells containing MR and in normal kidneys. MR antagonists and the end products of 11β-HSD attenuate these fibrogenic effects.
醛固酮（Aldo）可作为心血管和肾脏组织的致纤维增生因子。本研究检验了这样一个假说，即延长 Aldo 暴露能够直接诱导正常非高血压动物肾脏中的纤维性变化。含有 11β-羟类固醇脱氢酶（11β-HSD1）但不含盐皮质激素受体（MR）的永生化大鼠近端肾小管细胞（IRPTC）和含有 11β-HSD2 和 MR 的小鼠内髓集合管细胞（IMCD）接受了检测。将 Aldo 或皮质酮（10 nM）暴露于 IRPTC 48 h 后，用 Sirius red 染色评估胶原产生没有变化。相比之下，用 Aldo 处理的 IMCD 表现出胶原、纤维连接蛋白和结缔组织生长因子（CTGF）的表达显著增加，而单独的皮质酮没有影响。MR 拮抗剂 RU-318 和 11β-HSD 终产物 11-脱氧皮质酮显著减弱了 Aldo 诱导的胶原、纤维连接蛋白和 CTGF 的过度表达，但糖皮质激素受体拮抗剂 RU-486 没有作用。在体内，从接受连续 Aldo（8 μg·kg(-1)·day(-1)）输注 1 周的正常去肾上腺小鼠分离的肾脏中观察到早期纤维化变化，伴有胶原、纤维连接蛋白和 CTGF 表达升高。在皮质酮处理的小鼠中没有观察到这些变化。Aldo 诱导的变化在肾上腺完整的小鼠中和在用 RU-318 或 11-脱氧皮质酮处理的小鼠中减弱。因此，延长的 Aldo 暴露会导致含有 MR 的细胞和正常肾脏发生纤维性变化。MR 拮抗剂和 11β-HSD 的终产物减弱了这些纤维生成作用。
