MOLECULAR MECHANISM OF MESANGIAL DYSFUNCTION IN DIABETES

糖尿病肾小球系膜功能障碍的分子机制

• 批准号: 04671471
• 负责人: HANEDA Masakazu
• 金额: $ 1.34万
• 依托单位: SHIGA UNIVERSITY OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671471/
• 关键词: Diabetic nephropathy; Mesangial cells; Glomerular hyperfiltration; Angiotensin II; Atrial natriuretic peptide; Protein kinase C; Inositol 1, 4, 5-trisphosphate; 心房性ナトリウム利尿ペプチド; 心房性ナトリウム料尿ペプチド; グアニル酸シクラーゼ

Increase in glomerular filtration rates, glomerular hyperfiltration, is one of the major abnormalities in diabetic kidneys and is considered to be related to future development of diabetic nephropathy. We have previously shown that the contractile responsiveness of diabetic glomeruli to angiotensin II is reduced indicating the importance of mesangial cell dysfunction in diabetic glomerular hyperfiltration. The present study was performed to clarify the mechanism of this mesangial cell dysfunction. The following results were obtained ;1. In mesangial cells cultured under high glucose conditions, ANP-induced cGMP accumulation was enhanced.2. In contrast, inhibitory effects of angiotensin II on ANP-induced cGMP accumulation was reduced and the response of cellular IP3 to angiotensin II was also reduced.3. Protein kinase C (PKC) was activated in cells cultured under high glucose conditions and the translocation of PKC alpha and zeta was observed.4. Inhibition of PKC activities resulted in an amelioration of the reduction of angiotensin II action in cells cultured under high glucose conditions.These results indicate that, in mesangial cells cultured under high glucose conditions, and elevation of PKC activities may desensitize the action of angiotensin II and thus result in decreased contractile responsiveness of mesangial cells to angiotensin II.Therefore, mesangial cells in diabetic state may have a tendency to relax and this mesangial cell dysfunction, contributes to the development of glomerular hyperfiltration in diabetes.

肾小球滤过率增加，即肾小球超滤，是糖尿病肾脏的主要异常之一，被认为与糖尿病肾病的未来发展有关。我们先前已经表明糖尿病肾小球对血管紧张素II的收缩反应性降低，表明系膜细胞功能障碍在糖尿病肾小球高滤过中的重要性。本研究旨在阐明这种系膜细胞功能障碍的机制。获得了以下结果：1。高糖条件下培养的系膜细胞，ANP诱导的cGMP积累增强.与此相反，血管紧张素II对ANP诱导cGMP积累的抑制作用减弱，细胞内IP3对血管紧张素II的反应也减弱.高糖条件下培养的细胞蛋白激酶C（PKC）被激活，PKC α和zeta易位被抑制.抑制PKC活性可改善高糖条件下培养的系膜细胞对血管紧张素Ⅱ的反应性降低，提示高糖条件下培养的系膜细胞，PKC活性升高可使血管紧张素Ⅱ的反应性降低，从而降低系膜细胞对血管紧张素Ⅱ的收缩反应性。糖尿病状态下的系膜细胞可能具有松弛的趋势，并且这种系膜细胞功能障碍有助于糖尿病中肾小球超滤的发展。

项目成果

宇津 貴 他: "高糖濃度条件下培養メサンギウム細胞におけるプロテインキナーゼCの変化" 糖尿病. 36. (1993)

Takashi Utsu 等人：“高糖浓度条件下培养的肾小球系膜细胞中蛋白激酶 C 的变化”，糖尿病 36。

Haneda M,et al.: "The interaction between atrial natriuretic peptide and angiotensin II in cultured glomerular mesangial cells and its disturbance in diabetes." Experimental Nephrology. (印刷中).

Haneda M 等人：“培养的肾小球系膜细胞中心房钠尿肽和血管紧张素 II 之间的相互作用及其对糖尿病的干扰”。

Takashi Uzu, et al.: "Glucose enhances protein kinase C activity and induces translocation of PKC-alpha in cultured mesangial cells." J Japan Diab Soc. 36. 343-348 (1993)

Takashi Uzu 等人：“葡萄糖增强蛋白激酶 C 活性并诱导培养的系膜细胞中 PKC-α 的易位。”

Masakazu Haneda, et al.: "Alteration of mesangial response to ANP and angiotensin II by glucose." Kidney Int. 44. 518-526 (1993)

Masakazu Haneda 等人：“葡萄糖改变系膜对 ANP 和血管紧张素 II 的反应。”

Masakazu Haneda, et al.: "The interaction between atrial natriuretic peptide and angiotensin II in cultured glomerular mesangial cells and its disturbance in diabetes." Exp Nephrol. (in press).

Masakazu Haneda 等人：“培养的肾小球系膜细胞中心房钠尿肽和血管紧张素 II 之间的相互作用及其在糖尿病中的干扰。”