Altered Expression of COX-1, COX-2, and mPGES in Rats with Nephrogenic and Central Diabetes Insipidus

Title: Altered Expression of COX-1, COX-2, and mPGES in Rats with Nephrogenic and Central Diabetes Insipidus
Authors: Kotnik, Primoz; Nielsen, Jakob; Kwon, Tae-Hwan; Krzisnik, Ciril; Frokiaer, Jorgen; Nielsen, Soren
Publisher: American Journal of Physiology: Renal Physiology
Date Published: May 01, 2005
Reference Number: 690
Prostaglandins have an important role in renal salt and water reabsorption. PGE2 is the main kidney prostaglandin and is thought to be mainly produced in the kidney inner medulla (IM). There are indications that PGE2 synthesis in nephrogenic (NDI) and central (CDI) diabetes insipidus is altered. We hypothesize that the expression of the major PGE2 synthesis enzymes cyclooxygenases 1 and 2 (COX-1, COX-2) and membrane-associated PGE2 synthase (mPGES) is altered in the kidneys of rats with NDI and CDI. Wistar rats treated with lithium for 4 wk were used as the NDI model. One-half of the NDI model rats were additionally dehydrated for 48 h. Brattleboro (BB) rats that lack endogenous antidiuretic hormone were used as the CDI model. Expression and localization of COX-1, COX-2, and mPGES in IM, inner stripe of outer medulla (ISOM), and cortex were determined by immunoblotting and immunohistochemistry. In lithium-induced NDI, expression of COX-1, COX-2, and mPGES was markedly decreased in IM. In ISOM and cortex, COX-1 expression was marginally reduced and mPGES expression was unaltered. COX-2 expression was undetected in ISOM and marginally increased in cortex. Consistent with this, the density of COX-2-expressing cells in macula densa was significantly increased, indicating differential regulation of COX-2 in IM and cortex. Dehydration of NDI rats resulted in a marked increase in COX-2 immunolabeling in IM interstitial cells, and there was no significant change in COX-1 and mPGES expression in any kidney zone. Treatment of DDAVP in BB rats for 6 days resulted in a markedly increased expression of COX-1, COX-2, and mPGES in IM. In the cortex, there were no changes in the expression of COX-1 and mPGES, whereas COX-2 expression was decreased. These results identify markedly reduced expression of COX-1, COX-2, and mPGES in IM in lithium-induced NDI. Furthermore, there were major changes in the expression of COX-1, COX-2, and mPGES in rats with CDI.

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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Prostoglandins play an important role in the kidney’s ability to concentrate urine. The main prostoglandin found in the kidney is prostoglandin E2 (PGE2). Three enzymes help synthesize PGE2. They are cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2) and prostaglandin E synthase (PGES). COX-1 is believed to be constitutively expressed in the body, i.e., produced constantly regardless of physiological conditions or demand. COX-2 is expressed response to physiological stress.

PGE2 tones down the effect of the hormone, vasopressin (AVP) on osmotic water permeability in a part of the kidney called the collecting duct (CD). It does this by weakening the antidiuretic action that takes place there. That is, the way the kidney absorbs water involves osmosis – the flow of pure solvent through a permeable membrane in the direction of the less concentrated solution to the more concentrated solution. PGE2 helps moderate the absorption by causing a decrease in the movement of the water channel protein, aquaporin-2 (AQP2) from the cell interior to the cell membrane. (When AQP2 is in the cell membrane, it allows water to pass through the cell membrane and enter the cell.)

People with NDI are unable to concentrate urine efficiently. They void large amounts of dilute urine. Researchers have found elevated numbers of PGE2 in this dilute urine. Since PGE2 moderates the kidney’s urine concentrating ability, and elevated amounts of PGE2 in NDI patients’ urine indicates it is helping encourage large volumes of urine, researchers have tried treating NDI patients with COX-1 and COX-2 inhibitors on the idea that less COX-1 and COX-2 means less PGE2, which means less of a moderating effect on the kidney’s ability to concentrate urine. In short, the treatment is intended to decrease urine volume in NDI patients.

Kotnick, et al., designed a study to examine the numbers and location of COX-1 and COX-2 and PGES in three areas of the kidney: the inner medulla (IM), the outer medulla (OM) and the kidney cortex. They induced NDI in a group of mice by giving them large amounts of lithium. The researchers took half of the NDI group of mice and limited their water intake to produce a state of dehydration in them. (The research team also worked with a group of mice with central diabetes insipidus, but we will not cover this because our focus is NDI.)

In the NDI mice, the researchers determined that the number of COX-1, COX-2, and PGES in the IM were markedly decreased. In the OM and cortex the numbers of COX-1 were marginally reduced and the number of PGES remained the same. There were no detectable COX-2 in the OM, and COX-2 numbers increased slightly in the cortex.

The dehydrated NDI mice showed a significant increase in COX-2 in the IM and no significant change in COX-1 or PGES in any of the three kidney areas examined.

These results verify that the number of COX-1, COX-2 and PGES markedly decrease in the IM of lithium induced NDI mice. Thus, all three enzymes critical to PGE2 synthesis in the IM were reduced. This is likely due to compromised osmotic conditions in the inner tissues of the kidney. These findings indicate that COX-, COX- and PGES play a major role in the kidney’s ability to properly function.