Water intake during the development of renal hypertension (2K-1C) in mice

Abstract

SANTOS, C. M., R. F. JOHNSON, T. G. BELTZ, R. L. THUNHORST AND A. K. JOHNSON. Water intake during the development of renal hypertension (2K-1C) in mice. PHYSIOL BEHAV XX(X) XXX-XXX, 2005.-For both practical and methodological reasons, mice have been the most widely employed species for development of transgenic and gene knockin and knockout animals. However, basic behavioral and physiology control and regulatory mechanisms in mice are not well characterized. To broaden our understanding of the processes maintaining body fluid and blood pressure homeostasis in the mouse, the objectives of this study were to evaluate voluntary water, and sodium intakes during the development of renal hypertension and to examine the relationship between hypertension and the quantities of water and salt ingested. In male, C57BL/6J mice, two-kidney, one-clip renal hypertension (2K-1C) was induced, and water and 1.8% NaCl intakes were monitored for 2 weeks. At the end of this period, all animals received arterial catheters for direct recording of blood pressure. The mice that received renal artery clips were sorted into hypertensive (152 ± 4 mm Hg) and normotensive (122 ± 2 mm Hg) groups and were compared to control (117 ± 4 mm Hg) animals that underwent a sham renal clipping procedure. Hypertensive 2K-1C animals had significantly elevated water intake compared to control animals. On most of the postsurgical days, the normotensive 2K-1C animals did not display increased water intake in comparison to the control group. No significant effect was detected for 1.8% saline intake between any of the pairs of groups. In summary, the reduction of blood flow to a single kidney in the 2K-1C model of renal hypertension induces high blood pressure accompanied by sustained hyperdipsia in the mouse.

Introduction

For several decades in many areas of physiological research, including the study of body fluid and cardiovascular homeostasis, the rodent of choice has been the rat. In recent years, mice have emerged as the species for conducting experiments involving manipulation of the mammalian genome. To exploit the power inherent in mouse genetics and molecular biology and apply it to important functional issues, it is necessary to adapt many of the physiological models developed in rats to mice [1], [2], [3]. There are extensive studies in the rat on the relationship between blood pressure and the physiological and behavioral control systems maintaining body fluid balance [4], [5], [6], but there are relatively few investigations using mice. Because of possible species differences, it is important to understand the mechanisms of the physiological and behavioral regulation of body fluid balance and blood pressure in mice.

Angiotensin II (ANG II) mediates numerous behavioral and physiological responses such as increased water (thirst) and sodium (salt appetite) intake, the release of aldosterone and vasopressin, and constriction of vascular smooth muscle by direct actions and by sympathetic nervous system activation. Most of the actions of ANG II contribute collectively to expand extracellular and blood volume, and alter hemodynamics to produce both acute and chronic elevations in arterial blood pressure. One experimental model used to activate the renal renin-angiotensin system and investigate the pathophysiology of chronic high blood pressure is renovascular hypertension which can be produced by compromising blood flow to one of the two kidneys (2 kidney, one clip; 2K-1C). This model was first studied in dogs before it was adapted for rats. The method employs the constriction of the renal artery by a clip which restricts blood flow to one kidney while the contralateral kidney is left intact [7]. The earliest phase following placement of the clip is characterized by a rapid rise in plasma renin in response to low arterial pressure in one kidney. In the chronic phase, hypertension is maintained by a continuously activated renin-angiotensin system while the contralateral normal kidney prevents hypervolemia.

In studies of renal hypertension in rats, the rise in blood pressure has been reported to be accompanied by increased water and sodium intakes [8], [9], [10]. Constriction of one renal artery in rats produces salt appetite preceded by increased renin secretion and hypertension [11]. In contrast to most strains of rats, many strains of mice ingest minimal amounts of NaCl solutions ad libitum and in response to physiological challenges. ANG II produces increased sodium intake in mice when administrated centrally, but the peptide does not have the same effect when administered systemically [12], [13]. The objective of the present study was to investigate the effects of 2K-1C hypertension in mice and the effects of this treatment on thirst and salt appetite.