Mineralocorticoid receptor (MR) antagonist eplerenone and MR modulator balcinrenone prevent renal extracellular matrix remodeling and inflammation via the MR/proteoglycan/TLR4 pathway.

Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet.

Fecal ammonium in mice with CKD: gastrointestinal sequestration by sodium zirconium cyclosilicate.

Urinary [Formula: see text] excretion is decreased in chronic kidney disease (CKD), but very little is known about fecal [Formula: see text] excretion. Sodium zirconium cyclosilicate (SZC) is a cation exchanger that selectively captures K in the gastrointestinal tract. We investigated if SZC can sequester [Formula: see text] in vivo and evaluated the effect of SZC on fecal [Formula: see text] in a mouse model of CKD.

Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.

This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; ≥40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70 ml/min/1.73 m were randomized to once-daily AZD9977 100 mg or spironolactone 25 mg for 14 days, up-titrated to AZD9977 200 mg or spironolactone 50 mg for another 14 days.

Bilirubin levels and kidney function decline: An analysis of clinical trial and real world data.

Objective: To evaluate if previously found associations between low serum bilirubin concentration and kidney function decline is independent of hemoglobin and other key confounders.

Research Design And Methods: Clinical trial data from the SAVOR-TIMI 53 trial as well as the UK primary care electronic healthcare records, Clinical Practice Research Datalink (CPRD), were used to construct three cohorts of patients at risk of chronic kidney disease (CKD). The randomized clinical trial (RCT) cohort from the subset of SAVOR-TIMI 53 trial consisted of 10,555 type-2 diabetic patients with increased risk of cardiovascular disease.

Mineralocorticoid Receptor Antagonism Prevents the Synergistic Effect of Metabolic Challenge and Chronic Kidney Disease on Renal Fibrosis and Inflammation in Mice.

Obesity and/or metabolic diseases are frequently associated with chronic kidney disease and several factors associated with obesity may contribute to proteinuria and extracellular matrix production. Mineralocorticoid receptor antagonists have proven their clinical efficacy in diabetic kidney disease with preclinical data suggesting that they may also be efficient in non-diabetic chronic kidney disease associated to metabolic diseases. In the present study we developed a novel mouse model combining severe nephron reduction and High Fat Diet challenge that led to chronic kidney disease with metabolic alterations.

Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation.

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies.

Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption.

Background: The most profound effect of vasopressin on the kidney is to increase water reabsorption through V-receptor (VR) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of VR stimulation on kidney function, isolated from systemic effects.

Methods: The role of VR in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula.

Molecular tuning of farnesoid X receptor partial agonism.

The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice.

The selective mineralocorticoid receptor modulator AZD9977 reveals differences in mineralocorticoid effects of aldosterone and fludrocortisone.

Introduction:: AZD9977 is a novel mineralocorticoid receptor (MR) modulator, which in preclinical studies demonstrated organ protection without affecting aldosterone-regulated urinary electrolyte excretion. However, when tested in humans, using fludrocortisone as an MR agonist, AZD9977 exhibited similar effects on urinary Na/K ratio as eplerenone. The aim of this study is to understand whether the contradictory results seen in rats and humans are due to the mineralocorticoid used.

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion.

Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na delivery.

Key Points: Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels via both fast (24 h) and slow (5-7 days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo.

Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion.

Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia.

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator.

Aims: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977.

Methods: A first-in-human trial explored doses from 5 to 1200 mg.

Nephropathy in Pparg-null mice highlights PPARγ systemic activities in metabolism and in the immune system.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response, and development. Total-body deletion of the two Pparg alleles provoked generalized lipoatrophy along with severe type 2 diabetes. Herein, we explore the appearance and development of structural and functional alterations of the kidney, comparing Pparg null-mice to their littermate controls (carrying Pparg floxed alleles).

Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity.

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign.

The peroxisome proliferator-activated receptor α agonist, AZD4619, induces alanine aminotransferase-1 gene and protein expression in human, but not in rat hepatocytes: Correlation with serum ALT levels.

Alanine aminotransferase (ALT) in serum is the standard biomarker for liver injury. We have previously described a clinical trial with a novel selective peroxisome proliferator-activated receptor α (PPARα) agonist (AZD4619), which unexpectedly caused increased serum levels of ALT in treated individuals without any other evidence of liver injury. We pinpointed a plausible mechanism through which AZD4619 could increase serum ALT levels; namely through the PPARα-specific activation of the human ALT1 gene at the transcriptional level.

An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice.

Although blockade of the renin-angiotensin-system (RAS) has become standard therapy for diabetic nephropathy (DN), decline in kidney function towards end-stage renal disease is seen in many patients. Elevated plasma aldosterone often accompanies RAS blockade by a phenomenon known as "aldosterone escape" and activates the mineralocorticoid receptor (MR). We therefore examined whether addition of the MR antagonist eplerenone to an ACEI would enhance the efficacy in slowing the progression of DN.

LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim to develop dual PPARα/γ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual agonists glitazars. Recently, we described a new dual PPARα/γ ligand, LT175, with a partial agonist profile against PPARγ and interacting with a newly identified region of the PPARγ-ligand binding domain (1).

Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet.

Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice.

Tesaglitazar, a PPARalpha/gamma agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats.

The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas.

Gene expression analysis suggests that EBF-1 and PPARgamma2 induce adipogenesis of NIH-3T3 cells with similar efficiency and kinetics.

Differentiation of multipotent mesenchymal stem cells into lipid-accumulating adipocytes is a physiological process induced by transcription factors in combination with hormonal stimulation. We have used Affymetrix microarrays to compare the adipogenic differentiation pathways of NIH-3T3 fibroblasts induced to undergo in vitro differentiation by ectopic expression of early B cell factor (EBF)-1 or peroxisome proliferator-activated receptor (PPAR)gamma2. These experiments revealed that commitment to the adipogenic pathway in the NIH-3T3 cells was not reflected in gene expression until 4 days after induction of differentiation.

Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP.

SHP (small heterodimer partner) is an important component of the feedback regulatory cascade, which controls the conversion of cholesterol to bile acids. In order to identify the bona fide molecular targets of SHP, we performed global gene expression profiling combined with chromatin immunoprecipitation assays in transgenic mice constitutively expressing SHP in the liver. We demonstrate that SHP affects genes involved in diverse biological pathways, and in particular, several key genes involved in consecutive steps of cholesterol degradation, bile acid conjugation, transport and lipogenic pathways.

Identification of the human ApoAV gene as a novel RORalpha target gene.

Retinoic acid receptor-related orphan receptor-alpha (RORalpha) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that RORalpha regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that RORalpha also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels.

Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR alpha activation favors the formation of unconjugated bile acids.

In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic.