Zuo Yiqin, Gu Yong, Ma Ji, Lin Shantan
Department of Nephrology, Hua shan Hospital, Fudan University, Shanghai 200040, China.
Zhonghua Yi Xue Za Zhi. 2002 Feb 25;82(4):239-43.
To investigate the effect of selective cyclooxygenase (COX)2 inhibitor-meloxicam on the renal lesion of diabetic rats and its possible mechanism.
Twenty-nine rats were randomly divided into four groups: normal control rats (n = 6), streptozotocin (STZ)-induced diabetic rats without treatment (n = 8), STZ-induced diabetic rats treated with indomethacin (2 mg x kg(-1) x d(-1)) (n = 6), and STZ-induced diabetic rats treated with meloxicam (2 mg x kg(-1) x d(-1)) (n = 9). Sixteen weeks later, the blood sugar, blood urea nitrogen (BUN), and blood creatinine were examined. Radioimmunoassay was used to examine the prostaglandin(2) (PGE(2)) and Thromboxane B(2) (TXB(2)) in the urine. The expression of transforming growth factor -beta1 (TGF-beta1) and TGF-beta receptor type II (TbetaR2) of the renal cortex were measured by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Immuno-precipitation analysis was carried out to examine the protein level of angiotensin II type 1 (AT1) receptor. Periodic acid-Schiff staining was used to examine the morphological changes by light microscopy.
In the STZ-induced diabetic group, the blood levels of sugar, BUN, and creatinine were higher, and the creatinine clearance (Ccr) was remarkably higher in comparison with those in the normal control group (P < 0.05). Ccr was lower in diabetic rats treated with indomethacin and diabetic rats treated with meloxicam than in diabetic rats without treatment (P < 0.05). There was no difference of blood creatinie among these three groups. The blood sugar level in diabetic rats treated with meloxicam was lower than those in the diabetic rats treated with indomethacin and untreated group (all P < 0.05). The renal weight/body weight ratio was significantly higher in the untreated group than that in the control group. The PGE(2), TXB(2) and albumin levels in urine of STZ-induced diabetic rats were 1,641 +/- 288 pg/24 h 5,507 +/- 1,359 pg/24 h, and 46.3 +/- 9.5 microg/24 h respectively, much higher than those in meloxicam group (910 +/- 255 pg/24 h, 3,272 pg/24 h +/- 670 pg/24 h and 17.2 +/- 5.4 microg/24h respectively, all P < 0.01). The urine PGE(2) and albumin was 1,195 +/- 448 pg/24 h and 34.1 +/- 10.2 microg/24 h respectively in the indomethacin group. There was no difference in renal weight/body weight ratio and TXB(2) excretion between the untreated group and indomethacin group. The relative contents of TGF-beta1 and TbetaR2 mRNA expression in renal cortex of STZ-induced diabetic rats were 0.185 +/- 0.037 and 0.194 +/- 0.054, much higher than those in other groups. Glomerular hypertrophy, mesengial expansion, extracellular matrix accumulation, and sclerosis of partial glomeruli were seen in diabetic rats without treatment and those treated with indomethacin. The pathological changes were less in meloxicam group (P < 0.05).
The selective COX-2 inhibitor meloxicam significantly suppresses TGF-beta1 and TbetaR2 genes expression, elevates the protein level of AT1 receptor and attenuate the renal lesion caused by diabetes. TGF-beta1 and AT1 receptor may be involved in the mechanism concerned.
探讨选择性环氧化酶（COX）-2抑制剂美洛昔康对糖尿病大鼠肾脏病变的影响及其可能机制。
将29只大鼠随机分为四组：正常对照大鼠（n = 6）、链脲佐菌素（STZ）诱导的未治疗糖尿病大鼠（n = 8）、STZ诱导的用吲哚美辛（2 mg·kg⁻¹·d⁻¹）治疗的糖尿病大鼠（n = 6）以及STZ诱导的用美洛昔康（2 mg·kg⁻¹·d⁻¹）治疗的糖尿病大鼠（n = 9）。16周后，检测血糖、血尿素氮（BUN）和血肌酐。采用放射免疫分析法检测尿中前列腺素E₂（PGE₂）和血栓素B₂（TXB₂）。通过逆转录-聚合酶链反应（RT-PCR）分析检测肾皮质中转化生长因子-β1（TGF-β1）和Ⅱ型TGF-β受体（TβR2）的表达。进行免疫沉淀分析以检测血管紧张素Ⅱ1型（AT1）受体的蛋白水平。采用高碘酸-希夫染色通过光学显微镜检查形态学变化。
在STZ诱导的糖尿病组中，血糖、BUN和肌酐的血水平较高，与正常对照组相比，肌酐清除率（Ccr）显著更高（P < 0.05）。用吲哚美辛治疗的糖尿病大鼠和用美洛昔康治疗的糖尿病大鼠的Ccr低于未治疗的糖尿病大鼠（P < 0.05）。这三组之间血肌酐无差异。用美洛昔康治疗的糖尿病大鼠的血糖水平低于用吲哚美辛治疗的糖尿病大鼠和未治疗组（均P < 0.05）。未治疗组的肾重/体重比显著高于对照组。STZ诱导的糖尿病大鼠尿中PGE₂、TXB₂和白蛋白水平分别为1641±288 pg/24 h、5507±1359 pg/24 h和46.3±9.5 μg/24 h，远高于美洛昔康组（分别为910±255 pg/24 h、3272±670 pg/24 h和17.2±5.4 μg/24 h，均P < 0.01）。吲哚美辛组尿中PGE₂和白蛋白分别为1195±448 pg/24 h和34.1±10.2 μg/24 h。未治疗组和吲哚美辛组之间肾重/体重比和TXB₂排泄无差异。STZ诱导的糖尿病大鼠肾皮质中TGF-β1和TβR2 mRNA表达的相对含量分别为0.185±0.037和0.194±0.054，远高于其他组。在未治疗的糖尿病大鼠和用吲哚美辛治疗的糖尿病大鼠中可见肾小球肥大、系膜扩张、细胞外基质积聚和部分肾小球硬化。美洛昔康组的病理变化较轻（P < 0.05）。
选择性COX-₂抑制剂美洛昔康显著抑制TGF-β1和TβR2基因表达，提高AT1受体蛋白水平并减轻糖尿病引起的肾脏病变。TGF-β1和AT1受体可能参与其中相关机制。
