The Role of Nitric Oxide in the Expression of Renal Aquaporin 2 in a Cirrhotic Rat Model: Does an AVP-Independent Mechanism Exist for the Regulation of AQP2 Expression?

Abstract

The aquaporin (AQP) water channel is expected to play a decisive role of hyponatremia and water retention in cirrhotic patients. Despite the importance of the water channel, however, previous findings vary widely when it concerns AQP2 of the kidneys in subjects with cirrhosis. The purpose of this study was to investigate the expression of AQP2 in the distal renal tubule in cirrhosis, and the presence of the nitric oxide-AQP2 signaling pathway as a possible vasopressin-aquaporin-independent pathway. Sixty male Wister rats were assigned to six groups: (1) control; (2) TAA (thioacetamide); (3) TAA with nitric oxide donor; (4) TAA with nitric oxide inhibitor; (5) TAA with HMG CoA reductase inhibitor; (6) TAA with tetrahydrobiopterin. Immunohistochemical staining for AQP2, real-time polymerase chain reaction (PCR) for AQP2 and 3, citrulline assay, and renal cGMP concentration were measured. The AQP2-positivity of cirrhotic rats were higher than the controls (P < 0.05). The AQP2-positivity decreased in the nitric oxide donor group, but the proportion rose back up when the subjects were injected with the nitric oxide inhibitor (P < 0.05). The expression of AQP2 and AQP3 mRNA was also found to show an increase in the cirrhotic group as compared with the normal controls (P < 0.05). The cirrhotic group administered with nitric oxide donor showed a significant decline in the expression of the mRNA. The control group's cGMP concentration was lower than that of the cirrhotic group (P < 0.05), but a comparison of the two groups injected with nitric oxide modulators, such as statin and BH4, did not show significant differences in the cGMP concentration level. The expression of AQP2 of the kidneys increased in the cirrhotic rats. AQP2 had relations to the activity changes of nitric oxide synthetase.

Terlipressin Resolves Ascites of Cirrhotic Rats through Downregulation of Aquaporin 2

“…For example, AQP2 has been reported to be regulated by prostaglandin E 2 or nitric oxide synthetase. 30 The AQP1 level did not change after terlipressin administration in the present study, indicating that AQP1 may not be involved in the therapeutic mechanisms of terlipressin.…”

“…Terlipressin significantly increased fluid-excretion volume compared with normal control noncirrhotic group and the saline treated cirrhotic group. (B) Urine and blood osmotic pressures (mean ± SD) in the three study groups after 5 days' treatment ( a P < 0.05 compared with normal control noncirrhotic group; b P < 0.05 compared with saline-treated cirrhotic group; unpaired Student's t-test) 30 Normal …”

Nephrogenic Diabetes Insipidus – The Novelly Potential Therapeutic Drugs

“…Similarly, another study by Martin et al (Martin et al, 2002) showed that water deprivation induced the expression of endothelial NOS and neuronal NOS in the outer medulla as well as both the outer medulla and the papilla, respectively, which could be subsequently decreased by water loading. Other evidence further supporting the idea that NO-cGMP plays a role in water homeostatic mechanisms came from the fact that 1) VP specifically increases neuronal NOS expression levels in the renal outer medulla and papilla (Martin et al, 2002), 2) an increased expression of AQP2 within the kidneys of cirrhotic rats was found to correlate with the increasing activities of NOS (Jun et al, 2010), and 3) simultaneous disruption of all three NOS isoforms led to reduce membranous AQP2 expression associated with tubuloglomerular lesion formation, as well as marked hypotonic polyuria, polydipsia, and renal unresponsiveness to VP (Morishita et al, 2005), all of which are characteristics consistent with NDI. Thus, AQP2 expression and trafficking, which is chiefly regulated by VP, may be additionally stimulated by NO-cGMP activity.…”