How does aldosterone effect the kidneys

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Hypertension 52 , — Aldosterone induces a vascular inflammatory phenotype in the rat heart. Heart Circ. Physiol , H—H Rickard, A. Min, L. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Nakamura, Y. Small interventional studies in patients with chronic kidney disease have shown promising results, with a significant reduction of proteinuria associated with aldosterone antagonism, but large interventional trials that test the efficacy and safety of mineralocorticoid-receptor antagonists in chronic kidney disease are needed.

Abstract Aldosterone, a steroid hormone with mineralocorticoid activity, is mainly recognized for its action on sodium reabsorption in the distal nephron of the kidney, which is mediated by the epithelial sodium channel ENaC. The study of Kasal et al. It had been known that vascular damage by angiotensin II is mediated in part by macrophages and T-helper lymphocytes, while adoptive transfer of Tregs prevents angiotensin II action.

The main finding is the documentation that aldosterone enhances macrophage infiltration in the aorta and the renal cortex as well as infiltration of the aorta by T-cells.

Tregs in the renal cortex were diminished, while adoptive transfer of Treg prevented the adverse vascular and renal effects induced by aldosterone. This finding indicates that immunomodulatory interventions may interfere with aldosterone-induced vascular and renal damage.

Fujita et al. In a recent study [ 27 ] either a mineralocorticoid receptor blocker, a Rac1 inhibitor, a Rho-kinase inhibitor or the superoxide-dismutase-mimetic Tempol were administered to young uninephrectomized SD rats on high salt. Excessive salt intake induced hypertension and proteinuria with overexpression of SGK1 and activation of Rac1. This outcome was prevented both by the mineralocorticoid receptor blockade and by Rac1 inhibition, leading to the conclusion that activation of the mineralocorticoid receptor as well as Rac1 is involved in kidney injury from salt-induced hypertension.

The observation that adrenalectomy abrogated salt-induced proteinuria led to the further conclusion that Rac1 is an enhancer of aldosterone-induced mineralocorticoid receptor activation in the kidney—and possibly a future therapeutic target as well Figure 2.

Active Rac1 in turn activates Q17 the mineralocorticoid receptor MR. Reproduced from: Fujita Hypertension ;— Apart from glomerular effects, aldosterone affects non-glomerular renal structures as well; Fu et al. These and other findings led to the question whether mineralocorticoid receptor signalling is involved in models of primary renal disease as well. Wild-type mice treated with anti-GBM antibody developed glomerular crescents, severe proteinuria and increased serum Cystatin C.

Eplerenone-treated wild-type mice displayed similar proteinuria, but less Cystatin C concentration and less crescents. In experimental mesangial proliferative anti-Thy While mineralocorticoid receptor antagonists failed to prevent mesangiolysis, they inhibited MCP-1 expression, glomerular macrophage infiltration and activation of mesangial cells e. Apart from glomerular disease, acute kidney injury AKI has also been identified as a potential target for blockade by the mineralocorticoid receptor.

In the study of Barrera-Chimal et al. In untreated animals, this intervention caused ischaemia and subsequently CKD, i. Treatment with spironolactone, either before and remarkably also after ischaemia! Furthermore, a recent study confirmed an interesting relationship between aldosterone and klotho [ 31 ]; klotho hypomorphic mice had higher plasma aldosterone concentrations and this was partially reversed by a calcium-deficient diet.

It comes as a certain surprise that iron-induced renal damage is susceptible to mineralocorticoid receptor signalling as well. Naito et al. These adverse findings were markedly attenuated by iron restriction—pointing to a role of free radical damage Fenton reaction —and are of interest in view of past human biopsy findings [ 33 ] and experimental [ 34 ] data on the role of iron-restriction on mineralocorticoid receptor signalling and renal damage in five of six nephrectomized Sprague—Dawley rats.

Interestingly, the expression of the nuclear mineralocorticoid receptor and of SGK-1, a downstream effector of the mineralocorticoid receptor, was attenuated by iron restriction. Thus, the effect of iron restriction on renal damage and hypertension may in part be caused by inhibition of renal mineralocorticoid receptor signalling.

While in the past the inhibitors of the mineralocorticoid receptor were limited in number, it is of interest that novel mineralocorticoid receptor antagonists have recently been introduced [ 35 ]. One novel mineralocorticoid receptor antagonist SM was recently compared with spironolactone in a model of uninephrectomized rats on high salt and aldosterone infusion. The anti-hypertensive effect of this novel mineralocorticoid receptor antagonist was superior to that of spironolactone.

For therapeutic intervention, novel agents are on the horizon [ 36 ], e. Because of the homology of the enzymes responsible for aldosterone and cortisol synthesis, such a blockade is not specific, however, for aldosterone synthesis and will therefore also suppress cortisol release [ 37 ]. The characteristics of inhibitors of aldosterone synthase CYP11B2 , i. The novel orally active aldosterone synthase inhibitor LCI decreases dose-dependently the plasma aldosterone concentration and increases the plasma renin activity.

This first orally active aldosterone synthase inhibitor also impacts on the glucocorticoid axis, thus limiting to some extent this approach. In a randomized double-blind placebo and active-control phase 2 trial [ 39 ], the compound caused significant reduction of systolic blood pressure and ambulatory h-blood pressure. The renin—angiotensin—aldosterone system RAAS is inappropriately activated in obesity [ 40 ].

In pre-diabetic individuals inhibition of the RAAS protects against kidney disease. Interestingly, recent studies suggest that RAAS-inhibition protects also by reducing the incidence of diabetes.

Diabetes activates the renin—angiotensin system by the newly recognized cell surface receptor for succinate GPR91 [ 41 ]. Succinate is a signalling substance reflecting cell stress; in the distal nephron and collecting duct, it is a signal triggering renal fibrosis. GPR91 accumulates if energy supply and demand are out of balance, thus providing a link between inappropriate glycaemia control and activation of the RAAS [ 42 ]. The activation of the RAAS has consequences outside of the kidney as well: at a cellular level, angiotensin II and aldosterone cause insulin resistance by increasing oxidative stress, attenuating insulin signalling and thus decreasing glucose transport.

Aldosterone also diminishes glucose-stimulated insulin secretion, both in vivo and in vitro , through a mineralocorticoid receptor-independent mechanism [ 40 ].

In diabetes, Xue and Siragy [ 43 ] had provided evidence of an active local tissue-based RAAS and of local production of aldosterone in the kidney. It is mainly localized in the renal cortex and up-regulated by angiotensin II and low salt intake. It is regulated by low salt intake, angiotensin via angiotensin II type 1 receptor and hyperglycaemia, but the finding of such local production is not uniformly accepted.

Nevertheless using real-time immunohistochemistry staining RT—PCR and microdialysis techniques to assess CYP11B2, Xue had characterized the enzyme responsible for local aldosterone synthesis in the normal kidney. Using immunohistochemistry, the CYP11B2 enzyme was documented in the glomeruli and in adrenalectomized animals. It was also demonstrable in the kidney interstitium. The implications of this landmark study, documenting the existence of a local aldosterone system in the kidney, have so far not been completely clarified.

Local activation of renal cells is obviously important, because Lee et al. The levels of the synthase CYP11B2 and of the mineralocorticoid receptor were significantly higher in podocytes of diabetic animals and this was associated with increased apoptosis. Intrarenal aldosterone biosynthesis via CYP11B2, the enzyme responsible for synthesis of aldosterone in the glomeruli, and specifically in the podocytes of rat kidneys, is up-regulated in animals with insulin-dependent diabetes.

This point is of potential importance, because patients with diabetes usually tend to have low plasma-renin activity; this might not exclude a role of RAS-mediated effects, however, in view of the activation of the intrarenal renin—angiotensin system [ 45 ].

In experimental studies, the urinary excretion of aldosterone is increased in diabetic rats. In the interstitial fluid, 8-isoprostane, i. The adverse role of aldosterone in glomeruli exposed to hyperglycaemia has recently been shown by Toyonaga et al. The observation is all the more remarkable, since—despite hypoaldosteronaemia—spironolactone decreased proteinuria, ROS production and podocyte damage.

Renin is an enzyme that leads to a series of chemical reactions resulting in the production of angiotensin II , which in turn stimulate aldosterone release. Aldosterone causes an increase in salt and water reabsorption into the bloodstream from the kidney thereby increasing the blood volume, restoring salt levels and blood pressure. The symptoms include high blood pressure, low blood levels of potassium and an abnormal increase in blood volume.

Low aldosterone levels are found in a rare condition called Addison's disease. In Addison's disease, there is a general loss of adrenal function resulting in low blood pressure, lethargy and an increase in potassium levels in the blood see the article on Addison's disease for further information. About Contact Events News. Search Search.