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Low Tonicity Mediates a Downregulation of Cyclooxygenase-1 Expression by Furosemide in the Rat Renal Papilla

Hayo Castrop^*, Helga Vitzthum^*, Karl Schumacher, Frank Schweda^* and Armin Kurtz^*

Institutes of *Physiology and Anatomy, University Regensburg, Regensburg, Germany.

Correspondence to: Dr. Hayo Castrop, Institut für Physiologie, Universität Regensburg, D-93040 Regensburg, Germany. Phone: 49-941-9432962; Fax: 49-941-9434315; E-mail: wolf.castrop{at}vkl.uni-regensburg.de

ABSTRACT. 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. Male 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. The downregulation of mRNA was paralleled by a decrease of Cox protein in the collecting ducts and interstitial cells. Moreover, tissue prostaglandin E₂ (PGE₂) 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 PGE₂ content like furosemide. To investigate the influence of the osmolarity on the expression of Cox and the production of PGE₂ 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 PGE₂ concentrations in the kidney inner medulla. This effect could be related to the breakdown of the papillary osmotic gradient induced by loop diuretics.

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