What hormones regulate the reabsorption of sodium and water in the kidney to increase blood pressure?

Gitelman and Bartter Syndromes

Our understanding of renal sodium reabsorption and potassium excretion is, in part, a result of intense efforts to identify families with blood pressure and serum potassium levels that markedly deviate from the population means. Several of these traits have shown patterns consistent with classic Mendelian transmission within families, enabling genetic mapping and gene identification. Gitelman and Bartter syndromes, discussed in detail elsewhere in this volume, are excellent examples which have proved instructive for understanding magnesium homeostasis (Bartter et al 1962, Gitelman et al 1966).

It is now recognized that patients with Bartter’s ­syndrome have salt wasting due to defects in the thick ascending limb (TAL) of the loop of Henle (Figure 14.1). These genes include SLC12A1 which encodes the Na-K-2Cl cotransporter NKCC2 through which the apical entry of these ions from the lumen of the TAL occurs (Quaggin et al 1995); KCNJ1, which encodes the potassium channel ROMK and which mediates the return of potassium across the apical membrane (Ho et al 1993); and genes encoding either of two subunits of the chloride channel that mediates basolateral exit of chloride in the TAL (CLCNKB and BSND) (Kierferle et al 1994, Birkenhager et al 2001). As discussed above, this mechanism results in the asymmetric reabsorption of cations and anions in the TAL, with development of a lumen-positive potential that provides the electrical driving force for paracellular magnesium and calcium reabsorption. Mutations that cause Bartter syndrome result in homozygous loss of one of these gene products, with consequent massive salt wasting. Despite the fact that a very large fraction of renal magnesium reabsorption occurs in the TAL, patients with Bartter syndrome do not have the marked hypomagnesemia seen in patients with mutations in claudin 16 and 19, and indeed frequently have normal magnesium levels (Simon et al 1997). Those who do develop hypomagnesemia are most often those with mutations in CLCNKB, which also appears to play a role in the DCT. This surprising finding suggests either: (1) that loss of the electrical driving force for magnesium reabsorption in the TAL in Bartter syndrome leaves a sufficiently strong concentration gradient that the intact paracellular pathway can still reabsorb considerable magnesium, which is not believed to be the case; or (2) that the defect in Bartter syndrome results in secondary compensation that promotes increased magnesium reabsorption in other nephron segments, while mutations in claudin 16 and 19 do not. The severe salt wasting of Bartter’s syndrome strongly activates the renin-angiotensin system, markedly augmenting salt reabsorption in other nephron segments. In particular, there is expansion of the distal convoluted tubule, at least in mouse models of Bartter’s syndrome; because the DCT is the site of the magnesium channel TRPM6, it seems possible that up-regulation of this channel could augment magnesium reabsorption in Bartter’s syndrome in ways that would not occur in patients with claudin 16 and 19 mutations. Both explanations could of course contribute.

While Bartter’s syndrome is a disease of the TAL, Gitelman’s syndrome results from homozygous loss of function of SLC12A3, which encodes the thiazide-sensitive Na-Cl contransporter NCC in the distal convoluted tubule (DCT; Figure 14.2) (Simon et al 1996). Perhaps the most surprising feature resulting from these mutations in the renal salt reabsorption pathway is the uniform development of hypomagnesemia among affected patients (Gitelman et al 1966). This finding parallels the development of hypomagnesemia among patients taking thiazide diuretics, specific inhibitors of NCC, and the later observation of hypomagnesemia in mice with targeted mutations in SLC12A3. These observations indicate the important role of NCC activity in the normal maintenance of magnesium homeostasis. The molecular details of this mechanism are still a matter of uncertainty; however, it has become clear that while only a small fraction of magnesium reabsorption occurs in the DCT, this site plays a vital role in net magnesium balance. Two key observations provide insights to the likely explanations. First, the cation channel TRPM6, which localizes to the DCT, is the likely magnesium channel (see below) (Schlingmann et al 2002, Walder et al 2002). Second, for reasons that are as yet not understood, the mass of the DCT is highly malleable, and specifically varies with the activity of NCC. Thus, mutations in NCC that cause Gitelman’s syndrome result in loss of DCT mass (Schultheis et al 1998), while mutations in WNK4 that cause increased activity of NCC (see chapter on WNK kinases in this volume) cause increased DCT mass (Lalioti et al 2006), as do Bartter’s mutations that activate the renin-angiotensin system (Lu et al 2002). These observations afford the speculation that loss of NCC results in diminished DCT mass, and that this event has, as a secondary consequence, reduced net TRPM6 activity. Consistent with this possibility, the NCC deficient mouse has been shown to have markedly reduced TRPM6 expression (Nijenhuis et al 2005).

SUMMARY

Sodium pump activity drives renal sodium reabsorption and provides a potential mechanism by which altered regulation can contribute to hypertension. Altered regulation of the pump can be primary or secondary. In animal models, evidence consonant with a primary role of the pump attributable to allelic variation in the pump has been obtained in animal models. In the Dahl SS rat, this evidence is centered on polymorphism in the renal catalytic subunit of the pump but has been disputed. In SHR and New Zealand hypertensive rat models, positional mapping approaches point to an important hypertension locus in the region of the renal catalytic subunit gene, and in SHR there is a shift in subcellular targeting of the pump in the renal proximal tubule during the development. SHR also shows altered regulation of proximal tubule pump activity by dopaminergic signaling. Further work is required to determine whether alterations in pump function in these models are due to primary genetic variation in the gene encoding the renal catalytic unit of the pump, although this is consistent with available data. In human essential hypertension, many obstacles impede the identification of genes and their pathogenetic process in contributing to hypertension susceptibility, although in some hypertensive subgroups interesting parallels have been observed between rat models and human hypertension—including altered proximal tubule sodium handling and abnormal regulation of the renal sodium pump by dopamine signal transduction mechanisms.

VI 18-Oxocortisol as mineralocorticoid

As a mineralocorticoid, aldosterone is involved in renal sodium reabsorption, as opposed to atrial natriuretic peptide (ANP), which regulates sodium plasma levels. Thus, aldosteronism is a classic cause of hypertension. Glucocorticoid-suppressible aldosteronism (GSA), also known as glucocorticoid-remediable aldosteronism, is characterized by large decreases in aldosterone plasma levels and blood pressure after administration of glucocorticoids (dexamethasone).

18-Oxocortisol isolated from the urine of a subgroup of patients with GSA was found to be responsible for hypertension through its mineralocorticoid activity. The structure and pathway for the biosynthesis of 18-oxocortisol are still unclear. Structure analysis of 18-oxocortisol in comparison with cortisol, corticosterone, and aldosterone eliminated the idea that cortisol, in its conversion to 18-oxocortisol, requires the same transformation pathway that yields aldosterone from corticosterone, i.e., the conversion of the methyl group at C-18 to a C-18 aldehyde (see Fig. 7).

The normal enzymatic group of 17-hydroxylating species regulates adrenal cortex biosynthesis of cortisol in the zona fasciculata and of aldosterone in the zona glomerulosa. Within this framework, the possibility of interaction between cortisol and aldosterone synthase is not obvious. One hypothesis addressing this is based on the existence of a transitional zone between both zonae, in which fasciculata and glomerulosa cells are found together. The larger the transitional zone, the higher the plasma 18-oxocortisol level. This hypothesis is supported by the fact that aldosterone synthase very efficiently transforms cortisol (used as substrate) into 18-oxocortisol in in vitro incubations. 18-Hydroxycortisol, a putative intermediate between cortisol and 18-oxocortisol (similar to 18- hydroxycorticosterone in the transformation of corticosterone into aldosterone; see above), was also isolated from those incubations, and exhibited a high degree of mineralocorticoid activity.

A second and more recent and accepted hypothesis is based on the existence of an “abnormal” enzyme in the zona fasciculata; it produces 18-oxocortisol from cortisol, catalyzing the same kind of reactions seen with aldosterone synthase and corticosterone. This enzyme would be the product of a chimeric gene formed by the crossover of genetic material containing the promoter and some of the first exons of the CYP11B2 gene and some of the last exons of the CYP11B1 gene. As a result of this polymorphic gene, the enzyme obtained contains the catalytic properties of CYP11B2 and the adrenocorticotropic hormone (ACTH)-responsiveregulation of CYP11B1. However, this abnormal enzyme was found only in some patients carrying GSA, and not in all of them. This field is still open to future studies.

Standard Therapies

Symptomatic treatment and management of orthostatic hypotension include both non-pharmacological and pharmacological measures aimed at expanding blood volume and minimizing excessive pooling of blood. Therapy is generally based on the pathophysiology of the underlying disease Stumpf and Mitrrzyk (1994), Freeman (2003). Acute orthostatic hypotension due to hypovolemia may be treated with fluid repletion and an increase in sodium intake. Chronic orthostatic hypotension due to cardiac impairment, neuroendocrine disorders, and neurological dysfunction may involve treatment of the underlying disease.

Non-pharmacological measures for treating orthostatic hypotension include educating patients about triggering mechanisms, eliminating causative medications, and physical counter maneuvers such as skeletal muscle pumping and support garments Smit et al (1999). These measures can be implemented in the absence of pharmacological therapy Freeman (2003). When non-pharmacological measures fail, therapeutic interventions are required.

Pharmacotherapy of orthostatic hypotension, which is aimed at increasing plasma volume and vascular resistance, principally involves the use of synthetic mineralocorticoids, such as fludrocortisone acetate which reduces sodium loss and promotes water retention, and sympathomimetics Robertson and Davis (1995), Oldenberg et al (2002). Direct or indirect acting sympathomimetics may be employed alone or in combination with mineralocorticoid therapy. Direct acting sympathomimetics include midodrine, which is a peripheral-selective alpha-1 adrenoceptor agonist Oldenburg (2002). Ephedrine and pseudoephedrine are mixed alpha-adrenoceptor agonists that directly stimulate adrenoceptors and act indirectly by releasing norepinephrine from the postganglionic sympathetic neuronsRobertson and Davis (1995), Freeman (2003). The sympathomimetics, which cause venous and arterial constriction, can lead to supine hypertension.

Other agents used for the treatment of orthostatic hypotension include erythropoietin, vasopressin analogs, and caffeine. Erythropoietin may be used in anemic patients to increase red blood cells and cerebral oxygenation Hoeldtke and Streeten (1993). Vasopressin analogs, such as desmopressin, decrease nocturnal diuresis and improve morning orthostatic hypotension Mathias et al (1986). Caffeine, an adenosine receptor antagonist, reduces the vasodilation associated with postprandial hypotension. Indomethacin, which inhibits the synthesis of prostaglandins, may be administered to prevent vasodilatation.

Target Cells/Tissues and Functions

Ang II/AT1 axis mediates vasoconstriction, thirst, release of vasopressin and aldosterone, renal sodium reabsorption, fibrosis, inflammation, angiogenesis, vascular aging, and atherosclerosis. Ang II-induced effects included blood pressure control, increased drinking, adrenergic stimulation, modulation of ion pump and transporter activities in the gill, kidney, and intestine in fish, control of filtering nephron population in fish, and regulation of ventral skin absorption in amphibians [1]. Injection of Ang II significantly increases ventral skin drinking in the frog. Lamprey Ang II is a vasodepressor instead of a vasopressor when injected intra-arterially [2]. Intracerebroventricular (ICV) injection of Ang II into trout increases systemic blood pressure, heart rate, and ventilation rate. ICV injection of Ang II elicits tachycardia in contrast to bradycardia when injected peripherally. Central Ang II injection also inhibits the vagal-mediated baro-reflex, indicating brain RAS is involved in heart-rate control [9]. The AT2 receptor is mostly embryonic and expression is decreased in adults and is confined in certain tissues such as kidney. The effects of AT2 are often antagonistic to AT1, and activation of AT2 receptors usually indicates a pathophysiological condition of AT1-mediated action with potential harmful consequences. AT2 is abundantly expressed in the spleen of adult eel, which suggested an immune-related function [7].

3.5 Aging Kidney and the Interplay Between the Nitric Oxide and ANGII Systems

NO is vasodilatory, inhibits growth of contractile cells as well as extracellular matrix production, inhibits oxidative stress, and also inhibits renal sodium reabsorption. ANGII has opposing actions, since in addition to directly and indirectly promoting renal sodium retention and vasoconstriction, it also promotes cell growth, fibrosis, and oxidative stress and inflammation. Chronic NO deficiency develops in man and experimental animals in many types of CKD causing hypertension and a profibrotic state, which contribute to injury progression. There is also strong animal and clinical evidence that overactivity of intrarenal ANGII is part of the pathogenesis of hypertension and CKD.24 The possible contribution of NO deficiency/ANGII overactivity to development of age-dependent kidney damage and dysfunction and how this might relate to the sex differences have been discussed by some investigators.13 Total NO production falls in the aging male Sprague–Dawley rat and kidney injury develops rapidly, whereas in the aging Sprague–Dawley female, there is little CKD and total NO production is maintained (Fig. 7). Some of these sex differences are due to estrogen that exert multiple direct and indirect NO stimulatory actions.9

Cardiovascular

The renin–angiotensin system plays a central role in hypertension, mediating its effects through the peptide hormone angiotensin II, which increases arterial tone, stimulates aldosterone release, activates sympathetic neurotransmission, and promotes renal sodium reabsorption. Overactivation of the renin–angiotensin system therefore contributes to hypertension and its associated end-organ damage. The system can be inhibited at various points: ACE inhibitors reduce the conversion of angiotensin I to angiotensin II and angiotensin II receptor blockers antagonize the interaction of angiotensin II with the type-1 angiotensin II (AT1) receptor. However, both of these classes of agent interfere with the normal feedback mechanism to the juxtaglomerular apparatus in the kidneys and thus lead to a reactive rise in plasma renin activity, which can partially counteract their effects. Optimal blockade of the renin–angiotensin–aldosterone system should therefore be achievable by blocking the proximal step in the conversion of angiotensinogen to angiotensin I by directly inhibiting the action of renin, thus attenuating the reactive rise in plasma renin activity.

REDUCED INTRAVASCULAR VOLUME

There are several reasons for reduced extracellular fluid volume in patients with autonomic failure. First, impaired sympathetic activation directly decreases sodium reabsorption in the kidney.125 Second, impaired sympathetic activation inhibits renin secretion so that aldosterone is low and renal sodium reabsorption is decreased.121 Finally, other hormones involved in fluid homeostasis are also impaired in autonomic failure. For example, hypophyseal vasopressin release in response to hypotension is markedly reduced in patients with autonomic failure caused by CNS lesions (e.g., MSA).69 Low vasopressin levels prevent water conservation contributing to intravascular volume depletion.

Anemia is a common complication of autonomic failure, likely the result of inadequate erythropoietin levels.126,127 Although basal erythropoietin synthesis is not reduced in autonomic failure, the increase in erythropoietin synthesis in response to anemic hypoxia appears to be blunted in these patients. The reason for this abnormality is unknown, but in patients with autonomic failure, the lower the plasma norepinephrine levels in the upright posture, the lower the hemoglobin levels, suggesting some relationship between decreased sympathetic activity and reduced erythropoiesis.126 Similar to what occurs with the secretion of renin, another renal hormone, decreased renal sympathetic nerve activity may be the cause of impaired erythropoietin response to anemia in patients with autonomic failure. The modest decrease in red blood cell mass is another contributing factor to reduced intravascular volume.

Target Cells/Tissues and Functions

Ang II acts on the brain to control thirst, blood pressure, and ventilation rate, and also participates in the memory process (Figure 29.2). The Ang II/AT1 axis mediates vasoconstriction, thirst, release of vasopressin and aldosterone, renal sodium reabsorption, fibrosis, inflammation, angiogenesis, vascular aging, and atherosclerosis. AT2 is mostly embryonic and its expression decreases in adults. AT2 is confined in certain tissues such as kidney, and the expression and function are usually associated with pathophysiological conditions induced by AT1 signaling. The Ang (1–7)/Mas1 axis is also known to antagonize the effects of the AT1 axis, including anti-hypertrophic action, anti-thrombotic and anti-fibrotic effects, and vasodilation via stimulation of nitric oxide (NO) synthesis in endothelium and potentiation of the bradykinin effect. AT4/IRAP has a broad tissue distribution in the kidney, aorta, heart, liver, lung, uterus, adrenal gland, and brain, especially in neurons associated with memory function [9].

Perspectives

The demonstration that loss-of-function mutations in MR lead to salt-wasting and hypotension, while gain-of-function mutations lead to hypertension, is consistent with insights gained from all other Mendelian disorders primarily affecting blood pressure. Mutations which increase renal sodium reabsorption increase blood pressure, while those that decrease renal sodium reabsorption decrease blood pressure (Lifton et al 2001). Among these monogenic forms of hypertension, there is no clear relation between potassium handling, calcium handling, or vascular mechanisms to blood pressure, although these have all been proposed to be relevant to the development of hypertension.

The findings described above, coupled with the findings derived from patients with Liddle’s syndrome and arPHA1, add insight to questions concerning extrarenal and non-genomic actions of aldosterone. The finding that aldosterone blockade connotes significant morbidity and mortality benefits on patients with congestive heart failure and/or renal disease in the absence of a blood pressure altering effect (Pitt et al 1999, Sato et al 2003) has raised the question of whether aldosterone may have deleterious effects on cardiac physiology above and beyond its effects on renal sodium handling. The data from these Mendelian forms of HTN suggest that the primary effect of aldosterone in human disease is mediated via its effects on renal sodium handling. Patients with Liddle’s syndrome or hypertension exacerbated by pregnancy have significant cardiovascular and renal morbidity and mortality despite a virtual absence of circulating angiotensin II and aldosterone, while patients with pseudohypoaldosteronism type 1 have no evidence of structural heart disease despite high circulating levels of these hormones. Stated simply, excess renal sodium reabsorption is both necessary and sufficient for the induction of cardiovascular disease while aldosterone (or angiotensin II) is neither necessary nor sufficient. Whether aldosterone induces excess cardiovascular morbidity in the salt-overloaded condition above and beyond its effects on renal sodium reabsorption remains an open question.

Similarly, these data shed light on the role of non-genomic activities of aldosterone. Patients with PHA1 have some of the highest aldosterone levels ever observed, and yet, they are at risk of death from salt-wasting and hypotension. In contrast, patients with Liddle’s syndrome and hypertension exacerbated by pregnancy have minimal aldosterone production, and yet, they suffer from severe hypertension and cardiovascular disease (Warnock 2001). These findings suggest that the non-genomic mechanisms mediated by aldosterone via an as yet unidentified membrane receptor (Losel et al 2004), while they may have relevant short-term effects on cardiovascular indices such as vascular tone or heart rate, do not have major effects on the ultimate development of cardiovascular disease in these patients.