Benefits of the Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in Metabolic Syndrome-Related Heart Failure with Preserved Ejection Fraction.

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.

Understanding the opposite effects of sex hormones in mediating renal injury.

According to epidemiological studies, chronic kidney disease (CKD) affects more women than men, but the incidence of end-stage renal disease is higher in men than in women. However, most of these studies have not considered the incidence of CKD in women of reproductive or post-menopausal age, and even fewer with hormone replacement therapy. Some meta-analyses have reported an exacerbated progression of CKD in men compared with women. Consequently, in most of the experimental models of renal injury, men of reproductive age exhibit more abnormalities in renal function and structure that lead to greater progression to CKD than women, which suggests that these differences are mediated by sex hormones rather than by other factors. This review intends to show the mechanisms regulated by oestrogen or testosterone that may explain the different risks and evolution of renal diseases between men and women. Regardless of the initial cause of kidney disease, sex hormones have been implicated in modulating vascular tone, oxidative stress, inflammation and apoptosis. Finally, our previous study highlights the mechanisms by which the transition from acute kidney injury to CKD does not occur in female rats as commonly as it does in male rats. This review not only identifies sex differences in several kidney diseases but also supports potential therapeutic opportunities to reduce or prevent the progression of CKD and highlights the importance of considering sex differences in the design of any clinical study.

Resilience to acute kidney injury in offspring of maternal protein restriction.

Protein restriction (PR) during pregnancy induces morphofunctional alterations related to deficient nephrogenesis. We studied the renal functional and morphological significance of PR during pregnancy and/or lactation in adult male rat offspring and the repercussions on acute kidney injury (AKI) severity. Female rats were randomly assigned to the following groups: control diet during pregnancy and lactation (CC), control diet during pregnancy and PR diet during lactation (CR), PR during pregnancy and control diet during lactation (RC), and PR during pregnancy and lactation (RR). Three months after birth, at least 12 male offspring of each group randomly underwent either bilateral renal ischemia for 45 min [ischemia-reperfusion (IR)] or sham surgery. Thus, eight groups were studied 24 h after reperfusion: CC, CC + IR, CR, CR + IR, RC, RC + IR, RR, and RR + IR. Under basal conditions, the CR, RC, and RR groups exhibited a significant reduction in nephron number that was associated with a reduction in renal blood flow. Glomerular hyperfiltration was present as a compensatory mechanism to maintain normal renal function. mRNA levels of several vasoactive, antioxidant, and anti-inflammatory molecules were decreased. After IR, renal function was similarly reduced in all of the studied groups. Although all of the offspring from maternal PR exhibited renal injury, the magnitude was lower in the RC and RR groups, which were associated with faster renal blood flow recovery, differential vasoactive factors, and hypoxia-inducible factor-1α signaling. Our results show that the offspring from maternal PR are resilient to AKI induced by IR that was associated with reduced tubular injury and a differential hemodynamic response.

Pirfenidone prevents acute kidney injury in the rat.

BACKGROUND: Pirfenidone is an orally active drug used for the treatment of idiopathic pulmonary fibrosis to slow loss of lung function; it acts mainly through an antifibrotic effect but also possesses antioxidant and anti-inflammatory properties. We assessed the effect of prophylactic administration of pirfenidone on acute kidney injury due to bilateral renal ischemia. METHODS: Eighteen rats were included and divided in: 1) sham-operated rats (S), 2) rats underwent bilateral renal ischemia for 20 min (I/R), and 3) rats treated with pirfenidone 700 mg/kg/day 24 h before surgery and subjected to bilateral renal ischemia for 20 min (I/R + PFN). All the rats were euthanized and studied 24 h after renal reperfusion. RESULTS: As was expected, the I/R group exhibited a significant reduction in creatinine clearance, urinary output and renal blood flow, as well as extensive tubular injury. These alterations were associated with a significant decrease in urinary excretion of nitrites and nitrates (UNO2/NO3V). In the I/R + PFN group, recovery of renal function and UNO2/NO3V was observed, together with lesser histological signs of tubular injury compared to the I/R group. CONCLUSIONS: This study shows that prophylactic administration of pirfenidone prevented acute kidney injury due to bilateral ischemia in the rat. Recovery of NO production appears to be one of the mechanism of pirfenidone renoprotective effect. Our findings suggest that pirfenidone is a promising drug to reduce renal injury induced by I/R.

HSP72 is an early biomarker to detect cisplatin and acetaminophen nephrotoxicity.

OBJECTIVE: To evaluate whether the urinary HSP72 levels (uHSP72) are a useful biomarker for early diagnosis of acute kidney injury (AKI) induced by two widely used drugs: cisplatin and acetaminophen. MATERIALS AND METHODS: To analyze the time-course of nephrotoxic injury and uHSP72 levels, male Wistar rats were administered a single high dose of cisplatin (7 mg/kg) or acetaminophen (750 mg/kg) and were assessed at 6, 12, 24, 48, 72, 96 and 120 h. RESULTS: AKI induced by cisplatin was characterized by tubular injury that started at 6 h and was enhanced after 48 h. Plasma creatinine was increased only after 72 h. In contrast, uHSP72 levels were augmented after 6 h and were enhanced after 48 h of cisplatin administration, which was consistent with the tubular injury. In acetaminophen-induced AKI, the tubular lesions were less severe and predominantly characterized by tubular cell detachment. Interestingly, uHSP72 levels were increased after 6 h of acetaminophen injection and remained elevated at the following time points, reflecting the tubular injury, even in the absence of major functional changes. CONCLUSIONS: In two models of renal injury induced by nephrotoxic drugs, we showed that uHSP72 could be used as an early biomarker to detect subtle to severe tubular injury.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects.

Chronic kidney disease (CKD) is the leading complication in type 2 diabetes (T2D) and current therapies that limit CKD progression and the development of cardiovascular disease (CVD) include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Despite the introduction of these therapeutics, an important residual risk of CKD progression and cardiovascular death remains in patients with T2D. Mineralocorticoid receptor antagonists (MRAs) are a promising therapeutic option in diabetic kidney disease (DKD) owing to the reported effects of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells. In preclinical studies, MRAs consistently reduce albuminuria, CKD progression, and activation of fibrotic and inflammatory pathways. DKD clinical studies have similarly demonstrated that steroidal MRAs lead to albuminuria reduction compared with placebo, although hyperkalaemia is a major secondary effect. Non-steroidal MRAs carry a lower risk of hyperkalaemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with T2D. Encouragingly, other non-steroidal MRAs have anti-albuminuric properties in DKD. Whether or not combining MRAs with other renoprotective drugs such as SGLT2 inhibitors might provide additive protective effects warrants further investigation.

Neutrophil Gelatinase-Associated Lipocalin From Macrophages Plays a Critical Role in Renal Fibrosis Via the CCL5 (Chemokine Ligand 5)-Th2 Cells-IL4 (Interleukin 4) Pathway.

NGAL (neutrophil gelatinase-associated lipocalin; or lipocalin 2, Lcn2) is a novel mineralocorticoid target in the cardiovascular system. We showed that Lcn2 gene invalidation protects against proteinuria and renal injury upon mineralocorticoid excess and we hypothesized that NGAL produced from macrophages promotes the expression of chemoattractant molecules involved these renal lesions. The role of NGAL was analyzed using myeloid-specific (MΦ KO NGAL) Lcn2 knockout mice challenged with uni-nephrectomy, aldosterone, and salt (NAS) for 6 weeks. The role of the CCL5 (chemokine ligand 5) and IL4 (interleukin 4) in kidney fibrosis was studied by administration of the CCL5 receptor antagonist maraviroc or by injections of an anti-IL4 neutralizing antibody. In CTL mice, NAS increased the renal expression of extracellular matrix proteins, such as collagen I, αSMA, and fibronectin associated with interstitial fibrosis which were blunted in MΦ KO NGAL mice. The expression of CCL5 was blunted in sorted macrophages from MΦ KO NGAL mice challenged by NAS and in macrophages obtained from KO NGAL mice and challenged ex vivo with aldosterone and salt. The pharmacological blockade of the CCL5 receptor reduced renal fibrosis and the CD4+ Th cell infiltration induced by NAS. Neutralization of IL4 in NAS mice blunted kidney fibrosis and the overexpression of profibrotic proteins, such as collagen I, αSMA, and fibronectin. In conclusion, NGAL produced by macrophages plays a critical role in renal fibrosis and modulates the CCL5/IL4 pathway in mice exposed to mineralocorticoid excess.

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. We showed that the Mineralocorticoid Receptor antagonist canrenoate improved metabolic function, reduced albuminuria and prevented the synergistic effect of high fat diet on renal fibrosis and inflammation in chronic kidney disease mice.

Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics.

INTRODUCTION: Mineralocorticoid receptor (MR) antagonists (MRAs) provide cardiorenal protection. However steroidal MRAs might induce hyperkalemia and sex hormone-related adverse effects. Several novel non-steroidal MRAs are being developed that are highly selective for the MR and may have an improved safety profile. AREAS COVERED: This narrative review summarizes data from head-to-head comparisons of emerging non-steroidal MRAs with older steroidal MRAs, including pharmacological characteristics, pharmacokinetic properties, clinical outcomes, and safety, and highlights similarities and differences between emerging agents and established steroidal MRAs. EXPERT OPINION: Head-to-head comparisons in phase 2 trials suggest that the new non-steroidal MRAs exhibit at least equivalent efficacy to steroidal MRAs but may have a better safety profile in patients with heart failure and/or kidney disease. When also taking into account data from recent phase 3 placebo-controlled trials, these novel non-steroidal MRAs have the potential to provide a cardiorenal benefit above that of current optimized standard-of-care treatment in a high-risk population with reduced renal function, and with a lower risk of hyperkalemia. To optimize therapy, further research is needed to clarify the molecular differences in the mode of action of non-steroidal MRAs versus steroidal MRAs, and biomarkers that are predictive of MRA response need to be identified and validated.

Gender Differences in the Acute Kidney Injury to Chronic Kidney Disease Transition.

This study evaluated if there is a sexual dimorphism in the acute kidney injury (AKI) to chronic kidney disease (CKD) transition and the time-course of the potential mechanisms involved in the dimorphic response. Female and male rats were divided into sham-operated or underwent 45-min renal ischemia (F + IR, and M + IR). All groups were studied at 24-h and 1, 2, 3, or 4-months post-ischemia. Additionally, oophorectomized rats were divided into sham or IR groups. After 24-h, AKI extent was simllar in females and males, but female rats exhibited less oxidative stress and increased renal GSH content. After 4-months and despite similar AKI, the M + IR group developed CKD characterized by proteinuria, tubulointerstitial fibrosis, glomerular hypertrophy, increased oxidative stress and a reduction in HIF1α and VEGF from the 1st-month and persisting throughout the time-course studied. Interestingly, the F + IR group did not develop CKD due to lesser oxidative stress and increased eNOS, TGFß and HIF1α mRNA levels from the 1st-month after IR. Whereas, oophorectomized rats did develop CKD. We found a sexual dimorphic response in the AKI to CKD transition. Early antioxidant defense and higher TGFß, HIF1α and eNOS were among the renoprotective mechanisms that the F + IR group demonstrated.