Dahly-Vernon Annette J, Sharma Mukut, McCarthy Ellen T, Savin Virginia J, Ledbetter Steven R, Roman Richard J
Department of Physiology, and Kidney Disease Center, Medical College of Wisconsin, Milwaukee, WI 53226-4801, USA.
Hypertension. 2005 Apr;45(4):643-8. doi: 10.1161/01.HYP.0000153791.89776.43. Epub 2005 Feb 21.
This study examined the role of transforming growth factor-beta (TGF-beta) in altering the glomerular permeability to albumin (P(alb)) during hypertension development in Dahl salt-sensitive (Dahl S) rats and whether TGF-beta acts by inhibiting the glomerular production of 20-HETE. The results indicate that the renal expression of TGF-beta doubles in Dahl S rats fed a high-salt diet for 7 days, and this is associated with a marked rise in P(alb) from 0.19+/-0.04 to 0.75+/-0.01 and changes in the ultrastructure of the glomerular filtration barrier. Chronic treatment of Dahl S rats with a TGF-beta neutralizing antibody prevented the increase in P(alb) and preserved the structure of glomerular capillaries. It had no effect on the rise in blood pressure produced by the high-salt diet. In other studies, preincubation of glomeruli isolated from Sprague Dawley rats with TGF-beta1 (10 ng/mL) for 15 minutes increased P(alb) from 0.01+/-0.01 to 0.60+/-0.02. This was associated with inhibition of the glomerular production of 20-HETE from 221+/-11 to 3.4+/-0.5 mug per 30 minutes per milligram of protein. Pretreatment of Sprague Dawley glomeruli with a stable analog of 20-HETE, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid, reduced baseline P(alb) and opposed the effects of TGF-beta to increase P(alb). These studies indicate that upregulation of the glomerular formation of TGF-beta may contribute to the development of proteinuria and glomerular injury early in hypertension development in Dahl S rats by increasing P(alb) through inhibition of the glomerular production of 20-HETE.
本研究探讨了转化生长因子-β（TGF-β）在Dahl盐敏感（Dahl S）大鼠高血压发展过程中改变肾小球对白蛋白通透性（P(alb)）的作用，以及TGF-β是否通过抑制肾小球20-HETE的生成发挥作用。结果表明，给予高盐饮食7天的Dahl S大鼠肾脏中TGF-β的表达增加了一倍，这与P(alb)从0.19±0.04显著升高至0.75±0.01以及肾小球滤过屏障超微结构的改变有关。用TGF-β中和抗体长期治疗Dahl S大鼠可防止P(alb)升高，并保留肾小球毛细血管结构。它对高盐饮食引起的血压升高没有影响。在其他研究中，用TGF-β1（10 ng/mL）预孵育从Sprague Dawley大鼠分离的肾小球15分钟，可使P(alb)从0.01±0.01升高至0.60±0.02。这与肾小球20-HETE的生成从每30分钟每毫克蛋白质221±11抑制至3.4±0.5微克有关。用20-HETE的稳定类似物20-羟基二十碳-5(Z),14(Z)-二烯酸预处理Sprague Dawley大鼠肾小球可降低基线P(alb)，并对抗TGF-β增加P(alb)的作用。这些研究表明，TGF-β肾小球生成的上调可能通过抑制肾小球20-HETE的生成增加P(alb)，从而在Dahl S大鼠高血压发展早期促成蛋白尿和肾小球损伤的发生。
