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Regulation of renal water and sodium handling in complex kidney diseases

The effect of cyclooxygenase type 2 (COX-2) mediated prostaglandin synthesis on renal water and sodium regulation as well as function of urinary tract in obstructive kidney diseases

Rikke Nørregaard 


Obstruction of the urinary tract is a serious condition, which can occur in both children and   adults and it is a common cause of renal function impairment. The intraluminal pressure in the   ureter, pelvic and tubules increases immediately in response to ureteral obstruction and this   associated with reduced GFR and renal blood flow. In parallel, renal handling of water and   sodium is compromised. Thus in cases with bilateral ureteral obstruction this will then lead to   extensive changes in the systemic water and sodium balance due an impaired ability to   concentrate urine. The pathophysiology behind the loss of the urinary concentrating ability is   complex and previous studies suggest that reduced expression of renal aquaporins and sodium   transporters contribute to the impaired urinary concentrating capacity and salt wasting in   response to urinary tract obstruction. The mechanisms responsible for the dysregulation of   these transport proteins and channels remain incompletely understood; but previous studies   indicate that the COX-2-prostanoid pathway may contribute to renal function changes in   response to ureteral obstruction.    

This thesis was therefore divided into 2 main parts where the aims were: 1) To study the regulation of COX-2-mediated prostaglandin synthesis in the kidney and ureter after   bilateral ureteral obstruction in rats and 2) to investigate COX-2 mediated prostaglandin   synthesis for the renal water- and salt homeostasis and for the function of the ureter in   response to ureteral obstruction. The main findings of the studies, which have been published   in 3 papers are summarized below:    

1) COX-2 inhibition prevents downregulation of key renal water and sodium transport   proteins in response to bilateral ureteral obstruction  
Bilateral ureteral obstruction for 24 hours in rats demonstrated that COX-2, and not COX-1,   was markedly and selectively upregulated in inner medullary interstitial cells despite a   significant decrease of medullary tissue osmolality. Consistent with previous studies,   24hBUO was associated with severe downregulation of AQP2, AQP3, NKCC2, NHE3 and   NaPi-2. Importantly, selective COX-2 inhibition inhibited the increase of PGE2 excretion   after release and prevents downregulation of renal inner medullary AQP2 expression and   attenuates downregulation of NHE3 and NKCC2 expression at the mTAL. Thus, the present data suggest that increased PGE2 synthesis in response to acute BUO may play an important   role for the dysregulation of renal aquaporins and sodium transporters.    

2) COX-2 activity transiently contributes to increased water and NaCl excretion in the   polyuric phase after release of ureteral obstruction  
In the chronic polyuric phase 3 days after release of bilateral ureteral obstruction the   expression of the two cyclooxygenase (COX) isoforms changed inversely: Medullary COX-2   mRNA, protein, tissue distribution and activity increased in the chronic polyuric phase, while   COX-1 mRNA and protein expression decreased. Release of BUO was associated with   significant suppression of renal aquaporins and renal sodium transporters. Selective COX-2   inhibition normalized urinary PGE2 and PGI2 excretion and attenuated downregulation of   AQP2 and AQP3 while pAQP2 and NKCC2 remained suppressed. Parecoxib treatment did   not improve urinary concentrating capacity in response to 24h water deprivation. We   conclude that decreased NKCC2 and collapse of the inner medullary osmotic gradient   together with suppressed pAQP-2 are likely causes for the impaired urinary concentrating   capacity and that COX-2 activity is not likely to mediate these changes in the chronic postobstructive   phase after ureteral obstruction.    

3) Cyclooxygenase type 2 is increased in obstructed rat and human ureter and contributes   to pelvic pressure increase after obstruction  
Experimental occlusion of the rat ureter leads to a significant up-regulation of COX-2 at both   mRNA and protein levels in the proximal dilated ureter segment compared to the distal part of   the same ureter. COX-1 protein level and immunolabeling for COX-1 did not change in the   two ureter segments after obstruction. The expression of PGES was enhanced in the proximal   dilated part of the ureter compared to the distal ureter and urinary excretion of PGE2 increased   after release of obstruction. In both rat and human obstructed ureters, COX-2   immunoreactivity was detected in the surface epithelium (“urothelium”) and smooth muscle.   Furthermore, the expression of “dilatory” PGE2-EP2 and EP4 receptors and ‘constricting’   prostanoid receptors (TP and EP1) was demonstrated in control ureters. At the protein level   we demonstrated EP2 and TP receptors in obstructed ureters. A COX-2 specific blocker   significantly lowered intrapelvic pressure after obstruction, indicating that COX-2 activity   contributes to increased pelvic pressure during obstruction, indicating that COX-2 activity contributes to increased pelvic pressure during obstruction. At least 4 different prostanoid   receptors are expressed in the normal ureter. Future studies should clarify the involvement of   specific prostanoid receptor subtypes during acute ureteral obstruction. Elucidation of this   may have important clinical implications for the treatment of pain and function of ther ureter   related to pressure increase caused by obstruction.