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The importance of angiotensin II for the impaired vasopressin-regulated renal water and salt handling in rats with postobstructive kidney disease

Anja Møller Jensen

Summary

Urinary tract obstruction is a serious condition potentially leading to severe kidney damage and impaired renal function. In addition to characteristic hemodynamic changes, release of BUO leads to a striking vasopressin-resistant polyuria and natriuresis. Concurrently, major renal transport proteins are downregulated which probable is a crucial molecular mechanism contributing to the postobstructive urinary concentrating defect. Various hormones and signaling peptides are activated in the postobstructed kidney, including ANG II and several prostanoids. It is well described that ANG II plays a major role in the hemodynamic changes, and both ANG II and the prostanoids are import mediators of inflammation and fibrosis in the obstructed kidney. However, the influence of these hormones on renal tubular function is yet not fully understood
The overall aim of this PhD thesis was to elucidate the role of ANG II in postobstructive tubular dysfunction. Of particular interest were potential interactions between ANG II, vasopressin and the prostanoid system. Major findings were as follows: Paper 1: AT1 receptor blockade attenuated postobstructive polyuria, natriuresis, and phosphate loss 48 h after release of 24 h BUO. Moreover, AT1 receptor blockade attenuated the downregulation of major renal transport proteins and partly prevented COX2 induction. Paper 2: The vasopressin type 2 receptor (V2R) was distinctively downregulated in the postobstructed kidney 48 h after 24 h BUO and 24 h unilateral ureteral obstruction respectively. AT1 receptor blockade attenuated downregulation of V2R, pS256-AQP2, and Gsα protein in postobstructed kidney IM. Moreover, AT1 receptor blockade partially reversed obstruction-induced inhibition of NaF and forskolin-stimulated cAMP generation in inner medullary membrane fractions from BUO rats. Paper 3: COX2 inhibition caused further downregulation of AQP2 and pS256-AQP2 in the postobstructed kidney IM 48 h after 24 h BUO compared to non-treated BUO rats. No changes in V2R abundance or vasopressin-stimulated cAMP generation in kidney IM were observed in response to COX2 inhibition. In conclusion, we have shown that ANG II contributes significantly to the tubular dysfunctions and molecular changes observed in the postobstructed kidney. Interestingly, ANG II primarily influenced V2R and the downstream pathways including vasopressin-regulated transport proteins. Finally, ANG II-mediated COX induction seems not to be responsible for the molecular changes observed in response to AT1 receptor blockade as COX2 inhibition had either no influence or the opposite effect on V2R and vasopressin-regulated transport protein abundance.