Potential Benefit of Mineralocorticoid Receptor Antagonists in Kidney Diseases

1.1 MR expression in the kidney

Besides the well-known expression of MR in the so-called aldosterone-sensitive distal nephron (ASDN) encompassing DCT1-2, CNT, and CDD, MR is also expressed in a variety of other cell types within the kidney [1, 2, 3, 4, 5]. In basal condition, MR is expressed in the vasculature in both endothelium [6] and smooth muscle cells [1]. MR expression has also been reported in the mesangium [7], podocytes [8], fibroblasts [9], and immune cells (macrophages, dendritic cells, T lymphocytes) [10, 11, 12, 13]. In Figure 1, we summarize the effects reported for MR antagonists in different target cells within the kidney that represent potential beneficial mechanisms acting against kidney disease progression, and that will be detailed below. It is important to mention that MR expression might be upregulated in some pathological conditions such as diabetes [14], heavy proteinuria [15], vascular aging [16], and hypertension [17], leading to potential increased MR signaling. The specific physiological role of MR in the cells where its expression has been reported remains to be elucidated; however, it was recently proposed that MR in endothelial, smooth muscle, and inflammatory cells may be an evolutionary mechanism to prevent hemorrhage by promoting vasoconstriction and thrombosis and to promote wound healing by the activation of inflammation and vascular remodeling [18].

1.2 MR activation: what is the ligand?

The classical ligand of the MR is aldosterone, but glucocorticoids can bind with similar affinity with that of MR. Of note ligand-receptor dissociation is faster for glucocorticoid than aldosterone, resulting in higher transactivation potency for aldosterone as compared to glucocorticoids, especially at low concentration. However, a selectivity mechanism allows aldosterone to preferentially activate the MR in the presence of glucocorticoids, despite much higher local concentration of glucocorticoids than aldosterone. The 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts corticosterone/cortisol to compounds with low affinity for the MR [19]. The cellular aldosterone/glucocorticoid selectivity therefore depends on the expression level/activity of the HSD2. In the kidney, cells from the ASDN and endothelium express HSD2, while this is debated for the smooth muscle cells [20]. In podocytes, mesangial cells, and immune cells, for example, HSD2 is not expressed, therefore supporting the fact that glucocorticoids may be the main ligands of MR in these cells. It should be stressed, however, that there may be species differences as well as induction of HSD2 expression in some pathological conditions, allowing aldosterone to activate MR. This has not been carefully analyzed yet [1].

1.3 Major pathophysiological mechanisms involved in MR and kidney diseases

2.1 Benefit of MRA on acute kidney injury (AKI) induced by ischemia/reperfusion (IR)

A reduction of renal blood flow is occurring in several clinical settings, and this is a major cause of AKI. A number of studies in rodents and in the Large White Pig preclinical model have shown that MR antagonism with steroidal and nonsteroidal MRAs prevents and treats AKI induced by IR. In an early study, it was shown that spironolactone is a useful strategy to prevent the acute kidney dysfunction and tubular injury induced by bilateral renal IR injury in the rat [44]. The sustained reduction in renal blood flow observed after 24 hours in the IR-untreated rats was prevented in the spironolactone-treated groups. This was reproduced using nonsteroidal MRAs in both rats and mice [21, 22, 23] leading to the discovery of a novel underlying mechanism related to the limitation of oxidative stress and impaired endothelin-B receptor signaling [21, 22]. Importantly MRA also have curative effects when administered within the first 3 hours post ischemia-reperfusion [21, 45, 46]. The benefit of MR antagonists in ischemic AKI was translated into the Large White Pig preclinical model in which MR antagonism with soludactone (potassium canrenoate, a soluble MRA used in clinics) prevented the effects of AKI including kidney dysfunction and structural injuries [23].

2.2 AKI to CKD transition

In recent years, special focus has been given to the chronic consequences of an AKI episode. Several clinical and experimental studies have shown that AKI is linked with increased risk for CKD development.

In the rat, CKD progression induced by a single event of ischemic AKI (characterized by proteinuria, kidney dysfunction, and severe structural injury including interstitial fibrosis, glomerulosclerosis, tubule dilation, and podocyte injury) is prevented by spironolactone [45] and finerenone [22, 47]. MR antagonism also prevents CKD induced by a mild ischemic period even when administered 3 hours after the ischemia episode [48]. The underlying mechanisms rely on the limitation of inflammatory events and the promotion of repair mechanisms held by M2-type macrophages and interleukin-4 receptor signaling [34]. Importantly, these benefits are also observed in the Large White Pig model: short-term soludactone administration before/after the ischemic event indeed prevents CKD progression at 3 months, with a reduction in fibrosis and proteinuria and improved renal function [34]. The data indicate that MRA treatment is an encouraging therapeutic option to prevent the AKI to CKD transition which identifies the MR expressed in inflammatory cells as a specific target in this setting.

2.3 MR antagonism in kidney fibrosis and CKD progression

Kidney fibrosis is a common endpoint of CKD from different origins. Accumulating evidences indicate that aldosterone and/or MR signaling plays a key role in CKD development in a number of animal models including nephron reduction [49, 50], hypertensive models [51, 52], unilateral ureteral obstruction [53, 54], and mineralocorticoid/salt models [55]. MR antagonism not only prevents glomerulosclerosis in the remnant kidney model but also induces regression of glomerulosclerosis as evidenced by Aldigier et al. on kidney biopsy 4 weeks after spironolactone treatment initiation in rats already presenting CKD [56]. Eplerenone also limited proteinuria in this model [50]. Renal injury observed in the Dahl-sensitive rat upon salt loading is greatly limited by eplerenone [57, 58] and the nonsteroidal MRA CS-3150 [59]. This may be related to a direct effect on podocyte, as underlined by Shibata et al., involving activation of Rac1 and possible increased Rac1-mediated transactivation of the podocyte MR [60].

2.4 Benefit of MR blockade in diabetic nephropathy

The beneficial effects of MRA in different models of type I and type II diabetic nephropathy or kidney injury related to metabolic disorders have been reported. Spironolactone administration for 3 weeks reduced renal collagen deposition in STZ-induced diabetic rats [61]. This was thereafter reported for other MRAs such as eplerenone [62]. MRAs are also efficient in limiting progression of diabetic nephropathy in models of type 2 diabetes. Eplerenone reduced albuminuria, glomerular hypertrophy, and mesangial expansion in the db/db mouse model [62]. The novel nonsteroidal MRA AZ9977 has similar effects [63]. In the Otsuka Long-Evans Tokushima Fatty (OLETF) rats or Zucker obese rats, similar benefits have been reported after MRA treatment [64, 65].

2.5 Calcineurin inhibitor toxicity and kidney transplantation

Some studies showed a benefit of MR blockade in acute and chronic CsA nephrotoxicity, including effects on preventing structural and functional alterations [66, 67, 68]. The underlying mechanisms leading to this protection rely on hemodynamic effects (blunting the sustained vasoconstriction induced by CNI) [24, 68] or renal extracellular matrix remodeling [67]. The effect of MRA in experimental kidney transplantation has been tested in a model of chronic allograft dysfunction in the Dark-Agouti to Wistar-Furth rat with a reduced vasculopathy and glomerular macrophage influx and a trend to reduced proteinuria and glomerulosclerosis [69].

2.6 Glomerulonephritis and MR blockade

Although few studies have addressed this issue, it has been reported that spironolactone and the nonsteroidal MRA BR-4628 are beneficial in mouse models of glomerulonephritis [70, 71, 72]. The myeloid MR seems to play a key role in the kidney since genetic deletion of MR in myeloid cells, but not in podocyte, blunted glomerulonephritis development [8].