Potential Benefit of Mineralocorticoid Receptor Antagonists in Kidney Diseases

Since the last two decades, a major paradigm shift occurred in our understanding of the physiological and pathophysiological roles of the mineralocorticoid receptor (MR). Expression of the MR in cells/tissues not involved in sodium/potassium balance and extracellular volume homeostasis, i.e., the primary role of the aldosterone/MR complex, paved the way to the discovery of unsuspected implications of MR in a variety of cellular processes and pathological consequences. It also opens the possibility for quick translation to the bedside using available MR antagonists (MRAs) such as spironolactone, canrenone, or eplerenone or using the more recently developed various nonsteroidal MRAs that are not yet marketed. Landmark clinical trials like RALES, EPHESUS, or EMPHASIS well established that MRAs provide great benefits in patients with heart failure and spironolactone or eplerenone have been recommended in these patients. The deep understanding provided by preclinical studies in various domains stimulated the possibility to extend the use of MRAs to new fields, including renal diseases even if MRAs are currently contraindicated or used with great caution in patients with renal function impairment due to the higher risk of hyperkalemia associated with MRA therapy in this at-risk population. The present review presents preclinical data supporting potential indications in renal diseases

0307 Role of vascular mineralocorticoid receptor in renal injury induced by ischemia/reperfusion

IntroductionAcute kidney injury (AKI) is defined as an abrupt decrease (48h) in kidney function. One of the main causes of AKI is ischemia/reperfusion (I/R). AKI is related with high mortality, chronic kidney disease development and cardiac alterations like heart failure and arrhythmias. Mineralocorticoid receptor (MR) antagonism with spironolactone (Sp) prevents tubular injury and renal dysfunction induced by I/R in the rat. Although there is information supporting a role for aldosterone and MR in kidney injury, it remains unexplored the specific role of the MR expressed in the vasculature in mediating the deleterious effects of aldosterone during renal I/R.ObjectiveTo study the effect of inducing I/R in mice lacking the MR specifically in the endothelial cells or in the vascular smooth muscle cells.MethodsTo test if Sp is also able to prevent renal injury induced by I/R in the mice with the C57BL/6 background (same as MR KO mice) we included three groups of mice: 1) Sham, 2) I/R 20 min and 3) I/R 20 min + Sp pre-treatment. We analyzed the presence of renal dysfunction and inflammatory cytokines. In the MR KO mice, we will analyze the effect of MR deficiency after renal I/R in an acute phase (24h) and in chronic kidney disease development (after 4 weeks). In the acute studies the mechanisms that will be explored include: polarization of macrophages, endothelial injury and oxidative stress. In the chronic studies we will test if the wild type or MR knockout mice develop CKD as a consequence of renal I/R.ResultsMice underwent renal I/R developed injury characterized by increased serum creatinine and urea levels, urinary Hsp72 and elevation in the mRNA of TNF-alpha and MCP-1 pro-inflammatory cytokines. These alterations were prevented by the Sp pre-treatment.ConclusionThe protective effect of Sp against renal I/R that was previously reported in the rat is also observed in the C57BL/6 mice and supports the study of the MR KO mice in the renal I/R setting

Gene Expression Analysis Reveals the Cell Cycle and Kinetochore Genes Participating in Ischemia Reperfusion Injury and Early Development in Kidney

The molecular mechanisms that mediate the ischemia-reperfusion (I/R) injury in kidney are not completely understood. It is also largely unknown whether such mechanisms overlap with those governing the early development of kidney.We performed gene expression analysis to investigate the transcriptome changes during regeneration after I/R injury in the rat (0 hr, 6 hr, 24 hr, and 120 hr after reperfusion) and early development of mouse kidney (embryonic day 16 p.c. and postnatal 1 and 7 day). Pathway analysis revealed a wide spectrum of molecular functions that may participate in the regeneration and developmental processes of kidney as well as the functional association between them. While the genes associated with cell cycle, immunity, inflammation, and apoptosis were globally activated during the regeneration after I/R injury, the genes encoding various transporters and metabolic enzymes were down-regulated. We also observed that these injury-associated molecular functions largely overlap with those of early kidney development. In particular, the up-regulation of kinases and kinesins with roles in cell division was common during regeneration and early developmental kidney as validated by real-time PCR and immunohistochemistry.In addition to the candidate genes whose up-regulation constitutes an overlapping expression signature between kidney regeneration and development, this study lays a foundation for studying the functional relationship between two biological processes

The calcium-sensing receptor increases activity of the renal NCC through the WNK4-SPAK pathway

Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+. However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+. In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

International audienceChronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved

Editorial: Kidney and Distant Organ Crosstalk in Health and Disease

International audienceKidney disease is a health condition affecting a high number of patients with an estimated worldwide prevalence of 10% (Jager et al., 2019). Kidney dysfunction and the resulting accumulation of uremic toxins and chronic inflammation contribute to secondary injury in organs like the heart, vessels, lungs, gut, brain, liver, among others (Malek, 2018; Shang et al., 2020; Ambruso et al., 2021; Lai et al., 2021). On the other hand, kidney disease might be the result of co-morbidities or due to a primary insult in another organ (Ronco et al., 2018). The mechanisms by which this kidney-distant organ communication occurs remain partially understood. This Research Topic compiled original investigation and review papers that explored the connection between the kidneys and other organs/co-morbidities and result in the proposal of novel biomarkers, therapeutic strategies and bring new insights into the molecular mechanisms linking kidney disease with other organs.therapeutic strategies and bring new insights into the molecular mechanisms linking kidney diseasewith other organ

The mineralocorticoid receptor in chronic kidney disease

International audienceChronic kidney disease (CKD) is a major public health concern, affecting approximately 10% of the population worldwide. CKD of glomerular or tubular origin leads to the activation of stress mechanisms, including the renin–angiotensin–aldosterone system and mineralocorticoid receptor (MR) activation. Over the last two decades, blockade of the MR has arisen as a potential therapeutic approach against various forms of kidney disease. In this review, we summarize the experimental studies that have shown a protective effect of MR antagonists (MRAs) in nondiabetic and diabetic CKD animal models. Moreover, we review the main clinical trials that have shown the clinical application of MRAs to reduce albuminuria and, importantly, to slow CKD progression. Recent evidence from the FIDELIO trial showed that the MRA finerenone can reduce hard kidney outcomes when added to the standard of care in CKD associated with type 2 diabetes. Finally, we discuss the effects of MRAs relative to those of SGLT2 inhibitors, as well as the potential benefit of combination therapy to maximize organ protection