Low tonicity mediates a downregulation of cyclooxygenase-1 expression by furosemide in the rat renal papilla
Low tonicity mediates a downregulation of cyclooxygenase-1 expression by furosemide in the rat renal papilla
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DOI：
10.1097/01.asn.0000013296.11876.12
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发表时间：
2002-05-01
影响因子：
13.6
通讯作者：
Kurtz, A
中科院分区：
文献类型：
--
作者：
Castrop, H;Vitzthum, H;Kurtz, A
众所周知，袢利尿剂增强前列腺素类的肾排泄，因此，本研究旨在表征袢利尿剂对肾内环加氧酶表达的影响，环加氧酶是前列腺素类形成的关键酶。雄性SD大鼠连续6 d灌胃呋塞米（12 mg/kg·d）。分析不同肾区中环氧合酶-1和-2（考克斯-1和考克斯-2）的表达。呋塞米使皮质中考克斯-2 mRNA表达增加约2倍。但考克斯-1 mRNA的表达没有改变。在外髓。呋塞米对考克斯-1和考克斯-2 mRNA表达无影响。但在骨髓内层。呋塞米使考克斯-1和考克斯-2 mRNA水平分别降低至其对照水平的约30%和60%。集合管和间质细胞中的考克斯蛋白的减少抑制了mRNA的下调。此外，组织中的前列腺素E-2（PGE（2））浓度显着下降速尿约30%的控制水平。因此，呋塞米将尿渗透压从1550 mosmol/kg降至480 mosmol/kg。进一步考虑了作为呋塞米对考克斯表达的作用的可能介质的张力的影响。因此，通过第二次操作使用水负荷来降低髓张力。水负荷导致类似的乳头状考克斯mRNA表达和PGE（2）含量下降，如呋塞米。为了研究渗透压对体外条件下考克斯表达和PGE（2）产生的影响，将内髓集合管细胞与含有200 mmol/L至600 mmol/L浓度梯度的NaCl的培养基孵育，并在24 h和48 h后测定考克斯-1和考克斯-2 mRNA丰度。考克斯-1和考克斯-2 mRNA丰度与渗透压浓度平行变化。这些数据表明袢利尿剂降低了环加氧酶的表达，从而降低了肾内髓质组织中PGE（2）的浓度。这种作用可能与髓袢利尿剂引起的乳头状渗透梯度的破坏有关。
It is well known that loop diuretics enhance the renal excretion of prostanoids therefore, this study aimed to characterize the influence of loop diuretics on the intrarenal expression of cyclooxygenases, which are the key enzymes for prostanoid formation. Mate Sprague-Dawley rats were infused with furosemide (12 mg/kg per d) for 6 d. and the expression of cyclooxygenase-1 and -2 (Cox-1 and Cox-2) was analyzed in the different kidney zones. Furosemide increased Cox-2 mRNA expression approximately twofold in the cortex. but it left Cox-1 mRNA expression unaltered there. In the outer medulla. furosemide changed neither Cox-1 nor Cox-2 mRNA expression. In the inner medulla, however. furosemide decreased Cox-1 and Cox-2 mRNA levels to approximately 30% and 60% of their control levels, respectively. ne downregulation of mRNA was paralleled by a decrease of Cox protein in the collecting ducts and interstitial cells. Moreover, tissue prostaglandin E-2 (PGE(2)) concentrations in the papilla were markedly decreased by furosemide to about 30% of the control level. Furosemide lowered urine osmolality from 1550 mosmol/kg to 480 mosmol/kg: therefore. further consideration was given to the influence of tonicity as a possible mediator of the effects of furosemide on the Cox expression. Water loading was therefore used to reduce the medullary tonicity by a second maneuver. Water loading led to a similar reduction in papillary Cox mRNA expression and PGE(2) content like furosemide. To investigate the influence of the osmolarity on the expression of Cox and the production of PGE(2) under defined in vitro conditions, inner medullary collecting duct cells were incubated with culture medium containing graded amounts of NaCl ranging from 200 mmol/L to 600 mmol/L, and Cox-1 and Cox-2 mRNA abundance were determined after 24 h an 48 h. Cox-1 and Cox-2 mRNA abundance changed in parallel with the osmolarity. The data suggest that loop diuretics decrease the expression of cyclooxygenases and consequently tissue PGE(2) concentrations in the kidney inner medulla. This effect could be related to the breakdown of the papillary osmotic gradient induced by loop diuretics.