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Interactions between angiotensin II and arginine vasopressin in water homeostasis
co m m e nta r y
in rats with cachexia associated with chronic kidney disease.14 In conclusion, despite reports of the short- and intermediate-term success of ghrelin administration in treating anorexia and cachexia in ESRD patients, we must await results of studies on its long-term efficacy in improving appetite, weight gain, and lean body mass as well as quality of life. DISCLOSURE The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Mak RH, Cheung W, Cone RD et al. Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. Pediatr Nephrol 2005; 20: 427–431. Mak RH, Cheung W. Energy homeostasis and cachexia in chronic kidney disease. Pediatr Nephrol 2006; 21: 1807–1814. Mak RH, Cheung W. Therapeutic strategy for cachexia in chronic kidney disease. Curr Opin Nephrol Hypertens 2007; 16: 542–546. Kojima M, Hosoda H, Date Y et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660. Mak RH, Cheung W, Purnell J. Ghrelin in chronic kidney disease: too much or too little. Perit Dial Int 2007; 27: 51–55. Wynne K, Giannitsopoulou K, Small CJ et al. Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 2005; 16: 2111–2118. Ashby DR, Ford HE, Wynne KJ et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int 2009; 76: 199–206. Mak RH, Cheung W. Adipokines and gut hormones in end-stage renal disease. Perit Dial Int 2007; 27(Suppl 2): S298–S302. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2: 551–560. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003; 23: 7973–7981. Theander-Carrillo C, Wiedmer P, Cettour-Rose P et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006; 116: 1983–1993. Nagaya N, Moriya J, Yasumura Y et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110: 3674–3679. Vestergaard ET, Gormsen LC, Jessen N et al. Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling. Diabetes 2008; 57: 3205–3210. DeBoer MD, Zhu X, Levasseur PR et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 2008; 149: 827–835.
Kidney International (2009) 76
see original article on page 169
Interactions between angiotensin II and arginine vasopressin in water homeostasis Robert W. Schrier1 Mice deficient in the angiotensin II type 1a (AT1a) receptor demonstrate a vasopressin-resistant nephrogenic diabetes insipidus. These knockout mice exhibit a threefold increase in 24-h urine excretion. Neither 2 weeks of exogenous vasopressin nor 5 days of fluid restriction reversed this polyuric state. This nephrogenic diabetes insipidus was associated with reductions in adenylyl cyclase protein and in the phosphorylated mitogen-activated protein kinase extracellular signal–regulated kinase 1/2. The results support an important interaction between vasopressin and angiotensin II in maximal urinary concentration. Kidney International (2009) 76, 137–139. doi:10.1038/ki.2009.103
There is substantial evidence that arterial underfilling, due to either decreased cardiac output, e.g., heart failure, or systemic arterial vasodilation, e.g., cirrhosis, is associated with activation of the neurohumoral axis, including the sympathetic nervous system, the renin–angiotensin system, and arginine vasopressin (AVP). This neurohumoral response involves compensatory systemic vasoconstriction and renal sodium and water restriction in order to attenuate the arterial underfilling, that is, the so-called decreased effective arterial blood volume. What is not known is whether there is an interaction at the cellular and molecular levels between these responses to arterial underfilling. Li et al.1 (this issue) provide experimental evidence indicating an importance of angiotensin II in normal AVP-mediated urinary concentration. There are several potential mechanisms whereby angiotensin II could modulate water homeostasis, and thus angiotensin II 1Department of Medicine, University of Colorado
Denver, 12700 East 19th Avenue C281, Aurora, Colorado, USA Correspondence: Robert W. Schrier, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA. E-mail: Robert.Schrier@ UCdenver.edu
receptor knockout (KO) mice would be expected to have impaired urine-concentrating capacity. There is substantial evidence that angiotensin II stimulates the thirst center in the brain, thereby leading to increased thirst and water intake.2 Thus, the angiotensin II type 1a (AT1a) receptor KO mice might be expected to decrease their water intake unless other intervening effects occur. In this regard, Li et al.1 demonstrated that these KO mice actually have an increase, not a decrease, in water intake. Although somewhat controversial, there is evidence that angiotensin II may stimulate AVP release.3,4 Li et al.1 did demonstrate a decrease in basal plasma AVP concentrations in AT 1a receptor KO mice, as compared with wildtype mice. This, however, has not been a consistent finding in these AT1a receptor KO mice.5 In order to demonstrate partial central diabetes insipidus in the AT1a KO mice, for which Li et al.1 propose a role, it would be necessary to perform fluid restriction—which maximally concentrates urine in wild-type mice—and then administer exogenous AVP. Exogenous AVP would not increase urinar y osmolality further after such fluid restriction in wild-type mice; however, a further increment in urinary osmolality after fluid 137
com m enta r y
Arterial underfilling
↑ Vasopressin
↑ Angiotensin
V2 receptor
AT1a receptor
↑ Adenylyl cyclase
↑ cAMP
↑ AQP2 trafficking and expression
↑ Water transport
↑ Urinary concentration
Figure 1 | Potential pathway for interaction between angiotensin II and arginine vasopressin in the modulation of urinary concentration. AQP2, aquaporin 2, cAMP, cyclic adenosine monophosphate.
restriction with exogenous AVP would be expected in mice with partial central diabetes insipidus. As these studies were not performed, evidence for a role of AVPresponsive partial central diabetes insipidus cannot be established in these AT1a KO mice. A hemodynamic role of angiotensin II was apparent in these KO mice because their arterial blood pressures were significantly decreased compared with those of wild-type mice. Although renal hemodynamics were not reported in these KO mice, the observed decrease in renal arterial pressure was a likely factor in the observed diminished solute diuresis in response to sucrose administration, as compared with that of wild-type mice. In any case, increased solute excretion was excluded as a factor in the urine-concentrating defect in these AT1a KO mice. What was very clear in the Li et al.1 study was the presence of an AVP-resistant nephrogenic diabetes insipidus in these AT1a KO mice. The lower blood pressure in these KO mice could stimulate 138
thirst, independent of angiotensin II, and increased water ingestion. Increased water intake has been shown to cause a urineconcentrating defect.6 Decreasing the water intake in the AT1a KO mice to the level ingested by wild-type mice for 24 h or 5 days did not, however, correct the urine-concentrating defect. Although these results do not support a polydipsiarelated urine-concentrating defect, perhaps a longer period of normalizing fluid intake to the level ingested by wild-type mice may be necessary to improve the urine-concentrating defect in AT1a KO mice, which have had lifelong polydipsia. Of considerable interest was the observed defect in AVP signaling and aquaporin 2 (AQP2) trafficking to the apical membrane in the inner medulla of the AT1a KO mice. Although there was no evidence of decreased V2 vasopressin receptor binding in the inner medulla, there was a decline in adenylyl cyclase III and V/VI protein and in the phosphorylated mitogen-activated
protein kinase extracellular signal – regulated kinase 1/2. In contrast to the defect in the AVP-mediated AQP2 trafficking, the AVP stimulation of AQP2 protein expression was less disparate as compared with that in the wild-type mice. This result suggests that angiotensin II may exert a more important interaction with AVP in AQP2 trafficking to the apical membrane of the principal cells of the medullary collecting duct as compared with the AVP-mediated upregulation of AQP2 expression (Figure 1). There are previously published in vitro and in vivo results that suggest an interaction between AVP and angiotensin II. Angiotensin has been shown to enhance the in vitro AVP-dependent cAMP (cyclic adenosine monophosphate) accumulation in Chinese hamster ovary cells transfected with AT1a and V2 receptors.7 In primary cell culture of inner medullary collecting duct cells, angiotensin II and Desmopressin acetate both increased phosphorylation of AQP2 protein and its trafficking to the apical membrane. 8 Moreover, angiotensin receptor blockade in vitro has been shown to decrease urinary concentration and AQP2.9 Because there are many clinical disorders of water homeostasis in which arterial underfilling is present and associated with both increased AVP and angiotensin II, the potential interaction of these hormones at the molecular and cellular level has important implications.10 DISCLOSURE The author makes the following disclosures: educational grant from Astellas, review of applications with Amgen, and consulting agreement with Otsuka. ACKNOWLEDGMENTS This work was supported by a grant from the US National Institutes of Health (PO1 DK19928). The author would like to acknowledge Jan Darling for her assistance. REFERENCES 1.
2. 3.
Li XC, Shao Y, Zhuo JL. AT1a receptor knockout in mice impairs urine concentration by reducing basal vasopressin levels and its receptor signaling proteins in the inner medulla. Kidney Int 2009; 76: 169–177. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 1998; 78: 583–686. Henrich WL, Walker BR, Handelman WA et al. Effects of angiotensin II on plasma antidiuretic Kidney International (2009) 76
co m m e nta r y
4.
5.
6.
hormone and renal water excretion. Kidney Int 1986; 30: 503–508. Bonjour JP, Malvin RL. Stimulation of ADH release by the renin-angiotensin system. Am J Physiol 1970; 218: 1555–1559. Oliverio MI, Delnomdedieu M, Best CF et al. Abnormal water metabolism in mice lacking the type 1A receptor for ANG II. Am J Physiol Renal Physiol 2000; 278: F75–F82. Cadnapaphornchai MA, Summer SN, Falk S et al. Effect of primary polydipsia on
Kidney International (2009) 76
7.
8.
aquaporin and sodium transporter abundance. Am J Physiol Renal Physiol 2003; 285: F965–F971. Klingler C, Ancellin N, Barrault MB et al. Angiotensin II potentiates vasopressindependent cAMP accumulation in CHO transfected cells. Mechanisms of cross-talk between AT1a and V2 receptors. Cell Signal 1998; 10: 650–674. Le YJ, Song IK, Jang KJ et al. Increased AQP2 targeting in primary cultured IMCD cells in
response to angiotensin II through AT1 receptor. Am J Physiol Renal Physiol 2007; 292: F340–F350. 9. Kwon TH, Nielsen J, Knepper MA et al. Angiotensin II AT1 receptor blockade decreases vasopressininduced water reabsorption and AQP2 levels in NaCl-restricted rats. Am J Physiol Renal Physiol 2005; 288: F673–F684. 10. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol 2006; 17: 1820–1832.
139
in rats with cachexia associated with chronic kidney disease.14 In conclusion, despite reports of the short- and intermediate-term success of ghrelin administration in treating anorexia and cachexia in ESRD patients, we must await results of studies on its long-term efficacy in improving appetite, weight gain, and lean body mass as well as quality of life. DISCLOSURE The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Mak RH, Cheung W, Cone RD et al. Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. Pediatr Nephrol 2005; 20: 427–431. Mak RH, Cheung W. Energy homeostasis and cachexia in chronic kidney disease. Pediatr Nephrol 2006; 21: 1807–1814. Mak RH, Cheung W. Therapeutic strategy for cachexia in chronic kidney disease. Curr Opin Nephrol Hypertens 2007; 16: 542–546. Kojima M, Hosoda H, Date Y et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660. Mak RH, Cheung W, Purnell J. Ghrelin in chronic kidney disease: too much or too little. Perit Dial Int 2007; 27: 51–55. Wynne K, Giannitsopoulou K, Small CJ et al. Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 2005; 16: 2111–2118. Ashby DR, Ford HE, Wynne KJ et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int 2009; 76: 199–206. Mak RH, Cheung W. Adipokines and gut hormones in end-stage renal disease. Perit Dial Int 2007; 27(Suppl 2): S298–S302. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2: 551–560. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003; 23: 7973–7981. Theander-Carrillo C, Wiedmer P, Cettour-Rose P et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006; 116: 1983–1993. Nagaya N, Moriya J, Yasumura Y et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110: 3674–3679. Vestergaard ET, Gormsen LC, Jessen N et al. Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling. Diabetes 2008; 57: 3205–3210. DeBoer MD, Zhu X, Levasseur PR et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 2008; 149: 827–835.
Kidney International (2009) 76
see original article on page 169
Interactions between angiotensin II and arginine vasopressin in water homeostasis Robert W. Schrier1 Mice deficient in the angiotensin II type 1a (AT1a) receptor demonstrate a vasopressin-resistant nephrogenic diabetes insipidus. These knockout mice exhibit a threefold increase in 24-h urine excretion. Neither 2 weeks of exogenous vasopressin nor 5 days of fluid restriction reversed this polyuric state. This nephrogenic diabetes insipidus was associated with reductions in adenylyl cyclase protein and in the phosphorylated mitogen-activated protein kinase extracellular signal–regulated kinase 1/2. The results support an important interaction between vasopressin and angiotensin II in maximal urinary concentration. Kidney International (2009) 76, 137–139. doi:10.1038/ki.2009.103
There is substantial evidence that arterial underfilling, due to either decreased cardiac output, e.g., heart failure, or systemic arterial vasodilation, e.g., cirrhosis, is associated with activation of the neurohumoral axis, including the sympathetic nervous system, the renin–angiotensin system, and arginine vasopressin (AVP). This neurohumoral response involves compensatory systemic vasoconstriction and renal sodium and water restriction in order to attenuate the arterial underfilling, that is, the so-called decreased effective arterial blood volume. What is not known is whether there is an interaction at the cellular and molecular levels between these responses to arterial underfilling. Li et al.1 (this issue) provide experimental evidence indicating an importance of angiotensin II in normal AVP-mediated urinary concentration. There are several potential mechanisms whereby angiotensin II could modulate water homeostasis, and thus angiotensin II 1Department of Medicine, University of Colorado
Denver, 12700 East 19th Avenue C281, Aurora, Colorado, USA Correspondence: Robert W. Schrier, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA. E-mail: Robert.Schrier@ UCdenver.edu
receptor knockout (KO) mice would be expected to have impaired urine-concentrating capacity. There is substantial evidence that angiotensin II stimulates the thirst center in the brain, thereby leading to increased thirst and water intake.2 Thus, the angiotensin II type 1a (AT1a) receptor KO mice might be expected to decrease their water intake unless other intervening effects occur. In this regard, Li et al.1 demonstrated that these KO mice actually have an increase, not a decrease, in water intake. Although somewhat controversial, there is evidence that angiotensin II may stimulate AVP release.3,4 Li et al.1 did demonstrate a decrease in basal plasma AVP concentrations in AT 1a receptor KO mice, as compared with wildtype mice. This, however, has not been a consistent finding in these AT1a receptor KO mice.5 In order to demonstrate partial central diabetes insipidus in the AT1a KO mice, for which Li et al.1 propose a role, it would be necessary to perform fluid restriction—which maximally concentrates urine in wild-type mice—and then administer exogenous AVP. Exogenous AVP would not increase urinar y osmolality further after such fluid restriction in wild-type mice; however, a further increment in urinary osmolality after fluid 137
com m enta r y
Arterial underfilling
↑ Vasopressin
↑ Angiotensin
V2 receptor
AT1a receptor
↑ Adenylyl cyclase
↑ cAMP
↑ AQP2 trafficking and expression
↑ Water transport
↑ Urinary concentration
Figure 1 | Potential pathway for interaction between angiotensin II and arginine vasopressin in the modulation of urinary concentration. AQP2, aquaporin 2, cAMP, cyclic adenosine monophosphate.
restriction with exogenous AVP would be expected in mice with partial central diabetes insipidus. As these studies were not performed, evidence for a role of AVPresponsive partial central diabetes insipidus cannot be established in these AT1a KO mice. A hemodynamic role of angiotensin II was apparent in these KO mice because their arterial blood pressures were significantly decreased compared with those of wild-type mice. Although renal hemodynamics were not reported in these KO mice, the observed decrease in renal arterial pressure was a likely factor in the observed diminished solute diuresis in response to sucrose administration, as compared with that of wild-type mice. In any case, increased solute excretion was excluded as a factor in the urine-concentrating defect in these AT1a KO mice. What was very clear in the Li et al.1 study was the presence of an AVP-resistant nephrogenic diabetes insipidus in these AT1a KO mice. The lower blood pressure in these KO mice could stimulate 138
thirst, independent of angiotensin II, and increased water ingestion. Increased water intake has been shown to cause a urineconcentrating defect.6 Decreasing the water intake in the AT1a KO mice to the level ingested by wild-type mice for 24 h or 5 days did not, however, correct the urine-concentrating defect. Although these results do not support a polydipsiarelated urine-concentrating defect, perhaps a longer period of normalizing fluid intake to the level ingested by wild-type mice may be necessary to improve the urine-concentrating defect in AT1a KO mice, which have had lifelong polydipsia. Of considerable interest was the observed defect in AVP signaling and aquaporin 2 (AQP2) trafficking to the apical membrane in the inner medulla of the AT1a KO mice. Although there was no evidence of decreased V2 vasopressin receptor binding in the inner medulla, there was a decline in adenylyl cyclase III and V/VI protein and in the phosphorylated mitogen-activated
protein kinase extracellular signal – regulated kinase 1/2. In contrast to the defect in the AVP-mediated AQP2 trafficking, the AVP stimulation of AQP2 protein expression was less disparate as compared with that in the wild-type mice. This result suggests that angiotensin II may exert a more important interaction with AVP in AQP2 trafficking to the apical membrane of the principal cells of the medullary collecting duct as compared with the AVP-mediated upregulation of AQP2 expression (Figure 1). There are previously published in vitro and in vivo results that suggest an interaction between AVP and angiotensin II. Angiotensin has been shown to enhance the in vitro AVP-dependent cAMP (cyclic adenosine monophosphate) accumulation in Chinese hamster ovary cells transfected with AT1a and V2 receptors.7 In primary cell culture of inner medullary collecting duct cells, angiotensin II and Desmopressin acetate both increased phosphorylation of AQP2 protein and its trafficking to the apical membrane. 8 Moreover, angiotensin receptor blockade in vitro has been shown to decrease urinary concentration and AQP2.9 Because there are many clinical disorders of water homeostasis in which arterial underfilling is present and associated with both increased AVP and angiotensin II, the potential interaction of these hormones at the molecular and cellular level has important implications.10 DISCLOSURE The author makes the following disclosures: educational grant from Astellas, review of applications with Amgen, and consulting agreement with Otsuka. ACKNOWLEDGMENTS This work was supported by a grant from the US National Institutes of Health (PO1 DK19928). The author would like to acknowledge Jan Darling for her assistance. REFERENCES 1.
2. 3.
Li XC, Shao Y, Zhuo JL. AT1a receptor knockout in mice impairs urine concentration by reducing basal vasopressin levels and its receptor signaling proteins in the inner medulla. Kidney Int 2009; 76: 169–177. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 1998; 78: 583–686. Henrich WL, Walker BR, Handelman WA et al. Effects of angiotensin II on plasma antidiuretic Kidney International (2009) 76
co m m e nta r y
4.
5.
6.
hormone and renal water excretion. Kidney Int 1986; 30: 503–508. Bonjour JP, Malvin RL. Stimulation of ADH release by the renin-angiotensin system. Am J Physiol 1970; 218: 1555–1559. Oliverio MI, Delnomdedieu M, Best CF et al. Abnormal water metabolism in mice lacking the type 1A receptor for ANG II. Am J Physiol Renal Physiol 2000; 278: F75–F82. Cadnapaphornchai MA, Summer SN, Falk S et al. Effect of primary polydipsia on
Kidney International (2009) 76
7.
8.
aquaporin and sodium transporter abundance. Am J Physiol Renal Physiol 2003; 285: F965–F971. Klingler C, Ancellin N, Barrault MB et al. Angiotensin II potentiates vasopressindependent cAMP accumulation in CHO transfected cells. Mechanisms of cross-talk between AT1a and V2 receptors. Cell Signal 1998; 10: 650–674. Le YJ, Song IK, Jang KJ et al. Increased AQP2 targeting in primary cultured IMCD cells in
response to angiotensin II through AT1 receptor. Am J Physiol Renal Physiol 2007; 292: F340–F350. 9. Kwon TH, Nielsen J, Knepper MA et al. Angiotensin II AT1 receptor blockade decreases vasopressininduced water reabsorption and AQP2 levels in NaCl-restricted rats. Am J Physiol Renal Physiol 2005; 288: F673–F684. 10. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol 2006; 17: 1820–1832.
139