Ma L J, Nakamura S, Whitsitt J S, Marcantoni C, Davidson J M, Fogo A B
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561, USA.
Kidney Int. 2000 Dec;58(6):2425-36. doi: 10.1046/j.1523-1755.2000.00426.x.
Glomerular and vascular sclerosis increase with aging, and angiotensin inhibitors ameliorate progression of this injury. We investigated the potential for achieving regression of existing age-related sclerosis, and the mechanisms by which angiotensin type 1 receptor antagonist (AIIRA) may affect remodeling of this sclerosis. We focused on plasminogen activator inhibitor-1 (PAI-1) because it is directly induced by angiotensin, inhibits matrix degradation, and may thus be pivotal in remodeling.
Eighteen-month-old male Sprague-Dawley rats were treated with the AIIRA losartan (N = 8, 80 mg/L, dry weight), sacrificed at age 21 and 24 months, and compared with age-matched untreated controls (N = 15). Blood pressure and renal function were monitored, and morphological, biochemical, and molecular analyses were done on aorta and kidney.
Body weight increased in both groups. Mean arterial pressure (MAP) and serum creatinine remained normal (24-month MAP 115 +/- 8 vs. 113 +/- 6 mm Hg, controls vs. AIIRA, P = NS). Aorta wall thickness ratio was reduced by AIIRA at 21 and 24 months vs. age-matched controls (21 months 0. 12 +/- 0.01 vs. 0.15 +/- 0.01, P = 0.006; 24 months 0.10 +/- 0.005 vs. 0.14 +/- 0.003, AIIRA vs. controls, respectively, P = 0.0027). The aorta wall thickness ratio after treatment with AIIRA for six months was even lower than that of 18-month control rats (P = 0.018). AIIRA reduced proteinuria versus age-matched control at 24 months (253 +/- 62 vs. 390 +/- 51 mg/24 h, P = 0.0017). AIIRA at 24 months decreased glomerulosclerosis versus age-matched control (sclerosis index, 0 to 4+ scale: 0.06 +/- 0.02 vs. 0.49 +/- 0.12, P = 0.0082) to levels even lower than the 18-month baseline (0.37 +/- 0.14, P = 0.014). Renal collagen content increased with aging and was decreased by AIIRA at 24 months (5.0 +/- 0.7 vs. 3.1 +/- 0.5% collagen, P < 0.05). Apoptosis, assessed by TUNEL, was increased in tubular and interstitial cells in aging and was reduced by AIIRA versus control and baseline, respectively (TUNEL scoring, AIIRA 24 months 0.33 +/- 0.16 vs. 1.06 +/- 0.23 and 0.80 +/- 0.05, P < 0.05). PAI-1 mRNA in kidney was decreased at 24 months in AIIRA versus age-matched controls (PAI-1/GAPDH density ratio: AIIRA 24 months 0. 34 +/- 0.05 vs. 24-month controls 0.99 +/- 0.05, P < 0.05). Increased glomerular PAI-1 immunostaining with aging was decreased by AIIRA at 24 months versus age-matched controls, even below baseline (staining score 0 to 4+, 0.57 +/- 0.15 vs. control 0.90 +/- 0.07, P < 0.05; baseline 1.05 +/- 0.02, P < 0.01).
We conclude that AIIRA not only slows the progression of glomerular and vascular sclerosis in aging, but can also induce regression of these processes. The mechanisms appear to involve modulation of cortical cell turnover and inhibition of PAI-1 expression.
肾小球和血管硬化随年龄增长而加重，血管紧张素抑制剂可改善这种损伤的进展。我们研究了使现有与年龄相关的硬化消退的可能性，以及1型血管紧张素受体拮抗剂（AIIRA）影响这种硬化重塑的机制。我们重点关注纤溶酶原激活物抑制剂-1（PAI-1），因为它由血管紧张素直接诱导，抑制基质降解，因此可能在重塑过程中起关键作用。
对18月龄雄性Sprague-Dawley大鼠给予AIIRA氯沙坦（N = 8，80 mg/L，干重），在21和24月龄时处死，与年龄匹配的未治疗对照组（N = 15）进行比较。监测血压和肾功能，并对主动脉和肾脏进行形态学、生化和分子分析。
两组体重均增加。平均动脉压（MAP）和血清肌酐保持正常（24月龄时，对照组与AIIRA组的MAP分别为115±8 vs. 113±6 mmHg，P =无显著性差异）。与年龄匹配的对照组相比，AIIRA在21和24月龄时降低了主动脉壁厚度比（21月龄时，0.12±0.01 vs. 0.15±0.01，P = 0.006；24月龄时，0.10±0.005 vs. 0.14±0.003，AIIRA组与对照组相比，P = 0.0027）。AIIRA治疗6个月后的主动脉壁厚度比甚至低于18月龄对照大鼠（P = 0.018）。与年龄匹配的对照组相比，AIIRA在24月龄时降低了蛋白尿（253±62 vs. 390±51 mg/24 h，P = 0.0017）。与年龄匹配的对照组相比，AIIRA在24月龄时降低了肾小球硬化（硬化指数，0至4+评分：0.06±0.02 vs. 0.49±0.12，P = 0.0082），甚至低于18月龄基线水平（0.37±0.14，P = 0.014）。肾脏胶原蛋白含量随年龄增长而增加，AIIRA在24月龄时降低了该含量（胶原蛋白含量分别为5.0±0.7 vs. 3.1±0.5%，P < 0.05）。通过TUNEL评估的凋亡在衰老的肾小管和间质细胞中增加，AIIRA与对照组和基线相比分别降低了凋亡（TUNEL评分，AIIRA 24月龄时为0.33±0.16 vs. 1.06±0.23和0.80±0.05，P < 0.05）。与年龄匹配的对照组相比，AIIRA在24月龄时降低了肾脏中PAI-1 mRNA水平（PAI-1/GAPDH密度比：AIIRA 24月龄时为0.34±0.05 vs. 24月龄对照组为0.99±0.05，P < 0.05）。与年龄匹配的对照组相比，AIIRA在24月龄时降低了衰老导致的肾小球PAI-1免疫染色增加，甚至低于基线水平（染色评分0至4+，0.57±0.15 vs.对照组0.90±0.07，P < 0.05；基线为1.05±0.02，P < 0.01）。
我们得出结论，AIIRA不仅能减缓衰老过程中肾小球和血管硬化的进展，还能诱导这些过程的消退。其机制似乎涉及调节皮质细胞更新和抑制PAI-1表达。
