Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction

Abstract

The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT(1)-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 +/- 0.4 vs. 1.7 +/- 0.3 ml.min(-1).kg(-1)) and partially prevented the reduction in the expression of AQP2 (66 +/- 21 vs. 13 +/- 2%, n = 7; P < 0.05), NaPi-2 (84 +/- 6 vs. 57 +/- 10%, n = 7; P < 0.05), and NKCC2 (89 +/- 12 vs. 46% +/- 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 +/- 4 vs. 97 +/- 5 microl.min(-1).kg(-1), n = 7; P < 0.01) and the reduction in sodium reabsorption (433 +/- 62 vs. 233 +/- 45 micromol.min(-1).kg(-1), n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.

Analysis of Urinary and Plasma Electrolytes in a Rat Model of Unilateral Ureteric Obstruction (UUO)

“…Given the knowledge that the RAA system typically acts to preserve sodium and water, we might be left to conclude that in the UUO model, the resistance to AVP and subsequent diuresis must represent a powerful signal that overrides the pressor effect of local increases in RAA system activity. However, it is very interesting to note, that in bilateral ureteric obstruction in rats, angiotensin II actually mediates downregulation of certain aquaporin water channels and key renal Na + transporters [28]. This is an area which requires further investigation in a UUO model.…”

ANG II provokes acute trafficking of distal tubule Na+-Cl−cotransporter to apical membrane

“…ANG II is a potent vasoconstrictor and sodium-retaining hormone that plays a vital role in the regulation of blood pressure and is believed to contribute to the progression of cardiovascular and renal disease (24, 37). The role of ANG II in the regulation of NCC trafficking is not known; however, multiple studies have demonstrated the involvement of ANG II in the regulation of abundance of major renal sodium transporters such as ENaC, NKCC2, NHE3, and NCC (2,11,16). A role of ANG II in trafficking of the proximal tubule sodium transporter NHE3 has been demonstrated in a recent study from the McDonough laboratory: acute infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril provoked the redistribution of NHE3 to the base of the proximal tubule apical microvilli accompanied by increased proximal tubule flow and diuresis (18).…”

Cyclooxygenase 2 inhibition exacerbates AQP2 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney

“…Previous studies showed that at least part of the COX-2 induction is attributable to ANG II since ANG II receptor type 1A (AT1) blockade significantly reduced COX-2 abundance in the postobstructed kidney (21). Furthermore, AT1 receptor blockade attenuates downregulation of V2R and the vasopressin-regulated transport proteins pS256-AQP2, AQP2, and NKCC2 48 h after release of 24-h BUO (20,21).…”

“…Importantly, the vasopressin type 2 receptor (V2R) and vasopressin-regulated transport proteins are downregulated, causing vasopressinresistant polyuria (20,51,55). A number of hormone/signaling systems contribute to postobstructive kidney disease, including the prostanoid system (13,26,32,36) and the renin-angiotensin-system (RAS) (21,40,56).The most abundant prostaglandin in the kidney, prostaglandin E 2 (PGE 2 ), is involved in the regulation of kidney water and salt handling. In the medullary thick ascending limb (TAL), PGE 2 acutely blunts vasopressin-stimulated NaCl transport and cAMP generation (9, 46, 49) and the long-term effect of PGE 2 is downregulation of the vasopressin-regulated Na-K-2Cl cotransporter (NKCC2) (12).…”

“…Importantly, the vasopressin type 2 receptor (V2R) and vasopressin-regulated transport proteins are downregulated, causing vasopressinresistant polyuria (20,51,55). A number of hormone/signaling systems contribute to postobstructive kidney disease, including the prostanoid system (13,26,32,36) and the renin-angiotensin-system (RAS) (21,40,56).…”