Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.

Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial injury may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote cardiac mitochondrial quality control, we assessed whether these proteins were dysregulated during CRS-3-related cardiac depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of CRS-3. DUSP1 transgenic (DUSP1Tg) mice were protected from CRS-3-induced myocardial damage, as evidenced by their improved heart function and myocardial structure. CRS-3 induced the inflammatory response, oxidative stress and mitochondrial dysfunction in wild-type hearts, but not in DUSP1Tg hearts. DUSP1 overexpression normalized cardiac mitochondrial quality control during CRS-3 by suppressing mitochondrial fission, restoring mitochondrial fusion, re-activating mitophagy and augmenting mitochondrial biogenesis. We found that DUSP1 sustained cardiac mitochondrial quality control by binding directly to PHB2 and maintaining PHB2 phosphorylation, while CRS-3 disrupted this physiological interaction. Transgenic knock-in mice carrying the Phb2S91D variant were less susceptible to cardiac depression upon CRS-3, due to a reduced inflammatory response, suppressed oxidative stress and improved mitochondrial quality control in their heart tissues. Thus, CRS-3-induced myocardial dysfunction can be attributed to reduced DUSP1 expression and disrupted DUSP1/PHB2 binding, leading to defective cardiac mitochondrial quality control.

Dapagliflozin protects the kidney in a non-diabetic model of cardiorenal syndrome.

Cardiorenal syndrome encompasses a spectrum of disorders involving heart and kidney dysfunction, and sharing common risk factors, such as hypertension and diabetes. Clinical studies have shown that patients with and without diabetes may benefit from using sodium-glucose cotransporter 2 inhibitors to reduce the risk of heart failure and ameliorate renal endpoints. Because the underlying mechanisms remain elusive, we investigated the effects of dapagliflozin on the progression of renal damage, using a model of non-diabetic cardiorenal disease. Dahl salt-sensitive rats were fed a high-salt diet for five weeks and then randomized to dapagliflozin or vehicle for the following six weeks. After treatment with dapagliflozin, renal function resulted ameliorated as shown by decrease of albuminuria and urine albumin-to-creatinine ratio. Functional benefit was accompanied by a decreased accumulation of extracellular matrix and a reduced number of sclerotic glomeruli. Dapagliflozin significantly reduced expression of inflammatory and endothelial activation markers such as NF-κB and e-selectin. Upregulation of pro-oxidant-releasing NADPH oxidases 2 and 4 as well as downregulation of antioxidant enzymes were also counteracted by drug treatment. Our findings also evidenced the modulation of both classic and non-classic renin-angiotensin-aldosterone system (RAAS), and effects of dapagliflozin on gene expression of ion channels/transporters involved in renal homeostasis. Thus, in a non-diabetic model of cardiorenal syndrome, dapagliflozin provides renal protection by modulating inflammatory response, endothelial activation, fibrosis, oxidative stress, local RAAS and ion channels.

Diabetes modulation of the myocardial infarction-acute kidney injury axis.

As there is cross talk in functions of the heart and kidney, acute or chronic injury in one of the two organs provokes adaptive and/or maladaptive responses in both organs, leading to cardiorenal syndrome (CRS). Acute kidney injury (AKI) induced by acute heart failure is referred to as type 1 CRS, and a frequent cause of this type of CRS is acute myocardial infarction (AMI). Diabetes mellitus increases the risk of AMI and also the risk of AKI of various causes. However, there have been only a few studies in which animal models of diabetes were used to examine how diabetes modulates AMI-induced AKI. In this review, we summarize findings regarding the mechanisms of type 1 CRS and the impact of diabetes on both AMI and renal susceptibility to AKI and we discuss mechanisms by which diabetes modulates AMI-induced AKI. Hemodynamic alterations induced by AMI could be augmented by diabetes via its detrimental effect on infarct size and contractile function of the noninfarcted region in the heart. Diabetes increases susceptibility of renal cells to hypoxia and oxidative stress by modulation of signaling pathways that regulate cell survival and autophagy. Recent studies have shown that diabetes mellitus even at early stage of cardiomyopathy/nephropathy predisposes the kidney to AMI-induced AKI, in which activation of Toll-like receptors and reactive oxygen species derived from NADPH oxidases are involved. Further analysis of cross talk between diabetic cardiomyopathy and diabetic kidney disease is necessary for obtaining a more comprehensive understanding of modulation of the AMI-AKI axis by diabetes.

TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome.

There is a complex relationship between cardiac and renal disease, often referred to as the cardiorenal syndrome. Heart failure adversely affects kidney function, and both acute and chronic kidney disease are associated with structural and functional changes to the myocardium. The pathological mechanisms and contributing interactions that surround this relationship remain poorly understood, limiting the opportunities for therapeutic intervention. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed in injured kidneys and heart. The TWEAK-Fn14 axis promotes responses that drive tissue injury such as inflammation, proliferation, fibrosis, and apoptosis, while restraining the expression of tissue protective factors such as the anti-aging factor Klotho and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). High levels of TWEAK induce cardiac remodeling, and promote inflammation, tubular and podocyte injury and death, fibroblast proliferation, and, ultimately, renal fibrosis. Accordingly, targeting the TWEAK-Fn14 axis is protective in experimental kidney and heart disease. TWEAK has also emerged as a biomarker of kidney damage and cardiovascular outcomes and has been successfully targeted in clinical trials. In this review, we update our current knowledge of the roles of the TWEAK-Fn14 axis in cardiovascular and kidney disease and its potential contribution to the cardiorenal syndrome. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Vascular growth factors as potential new treatment in cardiorenal syndrome in diabetes.

BACKGROUND: Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In diabetes, chronic metabolic and haemodynamic perturbations drive endothelial dysfunction, inflammation, oxidative stress and progressive tissue fibrosis which, in turn, lead to heart and renal anatomo-functional damage. In physiology, vascular growth factors have been implicated in vascular homeostasis; their imbalance, in disease setting such as diabetes, leads to vascular dysfunction and cardiorenal damage. AIMS: To define the role of vascular growth factors and angiopoietins in cardiorenal syndrome. MATERIAL AND METHODS: We will focus on the two most studied vascular growth factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angpt). The balance and crosstalk between these growth factors are important in organ development and in the maintenance of a healthy vasculature, heart and kidney. The observed alterations in expression/function of these vascular growth factors, as seen in diabetes, are a protective response against external perturbations. RESULTS: The chronic insults driving diabetes-mediated cardiorenal damage results in a paradoxical situation, whereby the vascular growth factors imbalance becomes a mechanism of disease. Studies have explored the possibility of modulating the expression/action of vascular growth factors to improve disease outcome. Experimental work has been conducted in animals and has been gradually translated in humans. DISCUSSION: Difficulties have been encountered especially when considering the magnitude, timing and duration of interventions targeting a selective vascular growth factor. Targeting VEGF in cardiovascular disease has been challenging, while modulation of the Angpt system seems more promising. CONCLUSION: Future studies will establish the translatability of therapies targeting vascular growth factors for heart and kidney disease in patients with diabetes.

Heart, kidney and left ventricular assist device: a complex trio.

BACKGROUND: Heart failure (HF) is a complex syndrome affecting the whole body, kidneys included. The left ventricular assist device (LVAD) is a valid option for patients with very severe HF. Focusing on renal function, LVAD implantation could theoretically reverse the detrimental effects of HF syndrome on kidneys. However, implanting an LVAD is a high-risk surgical procedure, and LVAD patients have higher risk of bleeding, device thrombosis, strokes, renal impairment, multi-organ failure and infections. Furthermore, an LVAD has its own particular effects on the renal system. METHODS: In this review, we provide a comprehensive overview of the complex interaction between LVAD and the kidneys from the pathophysiological and clinical perspectives. An analysis of the different effects of pulsatile-flow and continuous-flow LVAD is provided. RESULTS: Despite their limitations, creatinine-based estimated glomerular filtration rate (eGFR) formulas help to stratify patients by their post-LVAD placement prognosis. Poor basal renal function, the onset of acute kidney injury or the need for renal replacement therapy after LVAD implantation negatively influences a patient's prognosis. LVAD can also prompt an improvement in renal function, however, with some counterintuitive effects on a patient's prognosis. CONCLUSION: It is still hard to say whether different trends in eGFR depend on different renal conditions before LVAD placement, on a patient's better overall status or on a particular patient management strategy before and/or after the device's implantation. Steps should be taken to solve this question because finding the best candidates for LVAD implantation is of paramount importance to ensure the best outcomes.

Association of hyponatraemia and renal function in type 1 cardiorenal syndrome.

BACKGROUND: Hyponatraemia predicts type 1 cardiorenal syndrome in acute decompensated heart failure patients, which associates with poor outcome. Recovery from hyponatraemia has been found to associate with better outcome in acute decompensated heart failure patients, but its prognostic value regarding renal function remains unknown. METHODS: We performed a secondary analysis of CARRESS-HF trial, and all patients included had worsening renal function (≥0.3 mg/dL increase in serum creatinine than the nadir). The serum sodium levels of patients were evaluated at baseline and day 4 and day 7 after randomization. Patients were grouped according to the status of hyponatraemia: recovery from hyponatraemia; no hyponatraemia; persistent hyponatraemia; and new-onset hyponatraemia. Their associations with persistent worsening renal function (serum creatinine ≥ 0.3 mg/dL higher than the nadir at discharge) were explored. RESULTS: A total of 118 patients suffered from persistent worsening renal function. Baseline hyponatraemia was not associated with persistent worsening renal function (odds ratio = 0.495, P = .086). Patients in the recovery from hyponatraemia group had a lowest risk of persistent worsening renal function among the study population. Further, baseline serum sodium level was not associated with the risk of persistent worsening renal function (odds ratio = 1.055, P = .233), while the increases in serum sodium level at day 4 (odds ratio = 0.858, P = .003) and at day 7 (odds ratio = 0.821, P < .001) significantly predicted a lower risk of persistent worsening renal function. CONCLUSIONS: Recovery from hyponatraemia associates with a lower risk of persistent worsening renal function, suggesting that hyponatraemia correction may improve renal outcomes in acute decompensated heart failure patients with type 1 cardiorenal syndrome.

The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease.

BACKGROUND: Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. METHODS: Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. RESULTS: Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 µg/kg in the adenine-induced RF mouse model. At a high concentration of 100 µg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-ß, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. CONCLUSION: Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.

N-acetyl-b-D-glucosaminidase: A potential cardiorenal biomarker with a relevant impact on ICD shock therapies and mortality.

AIMS: Chronic heart failure may lead to chronic kidney disease. Previous studies suggest tubular markers N-acetyl-b-D-glucosaminidase (NAG) and Kidney-injury-molecule-1 (KIM-1) as potential markers for the cardiorenal syndrome (CRS). The prognostic value of NAG and KIM-1 regarding implantable cardioverter defibrillator (ICD) shock therapies is unknown. METHODS: We included 314 patients with an ICD and collected plasma and urine samples. Urine-values of NAG and KIM-1 got related to urinary creatinine. Outcomes of interest were sustained adequate shock therapies and a combined endpoint of all-cause mortality, rehospitalisation due to congestive heart failure and adequate shock therapies. Follow up time was 32 months (IQR 6-35 months). RESULTS: KIM-1 and NAG were positively correlated with NT-proBNP (KIM-1: r = .34, P < .001; NAG: r = .47, P < .001). NAG was significantly elevated in patients with primary prevention compared with secondary prevention ICD indication (P = .003). According to Kaplan Meier analysis, NAG as well as NT-proBNP were significant predictors for adequate ICD shock therapies and for the combined endpoint (each P < .001). Elevated KIM-1 showed no significant differences (each P = n.s.). In multivariate cox regression analysis, NAG as well as NT-proBNP were both independent predictors for adequate ICD shock therapies as well as the combined endpoint, beside ejection fraction <35% (each P < .05). Diabetes, primary prevention ICD indication, coronary artery disease, eGFR and age were no significant predictors for both endpoints (each P = n.s.). CONCLUSION: Similar to NT-proBNP, NAG showed promising value for overall prognostication in ICD patients. Especially, NAG seems to incorporate an additional prognostic value regarding occurrence of ICD shock therapies.

Mechanisms of kidney dysfunction in the cirrhotic patient: Non-hepatorenal acute-on-chronic kidney damage considerations.

Renal dysfunction is a common finding in cirrhotic patients and has a great physiologic, and therefore, prognostic relevance. The combination of liver disease and renal dysfunction can occur as a result of systemic conditions that affect both the liver and the kidney, although primary disorders of the liver complicated by renal dysfunction are much more common. As most of the renal dysfunction scenarios in cirrhotic patients correspond to either prerenal azotemia or hepatorenal syndrome (HRS), physicians tend to conceive renal dysfunction in cirrhotic patients as mainly HRS. However, there are many systemic conditions that may cause both a "baseline" chronic kidney damage and a superimposed kidney dysfunction when this systemic condition worsens. The main aim of this article is to review some of the most important non prerenal non-HRS considerations regarding acute on chronic kidney dysfunction in cirrhotic patients, including renal manifestation of related to non-alcoholic steatohepatitis (NASH) viral hepatitis, the effect of cardiorenal syndrome in cirrhotics and corticosteroid-deficiency associated renal dysfunction.

Heart-kidney interactions: mechanistic insights from animal models.

Pathological changes in the heart or kidney can instigate the release of a cascade of cardiorenal mediators that promote injury in the other organ. Combined dysfunction of heart and kidney is referred to as cardiorenal syndrome (CRS) and has gained considerable attention. CRS has been classified into five distinct entities, each with different major pathophysiological changes. Despite the magnitude of the public health problem of CRS, the underlying mechanisms are incompletely understood, and effective intervention is unavailable. Animal models have allowed us to discover pathogenic molecular changes to clarify the pathophysiological mechanisms responsible for heart-kidney interactions and to enable more accurate risk stratification and effective intervention. Here, this article focuses on the use of currently available animal models to elucidate mechanistic insights in the clinical cardiorenal phenotype arising from primary cardiac injury, primary renal disease with special emphasis of chronic kidney disease-specific risk factors, and simultaneous cardiorenal/renocardiac dysfunction. The development of novel animal models that recapitulate more closely the cardiorenal phenotype in a clinical scenario and discover the molecular basis of this condition will be of great benefit.

Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. Forty-one percent of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.

Protein biomarkers for cardiorenal syndrome.

INTRODUCTION: The term cardiorenal syndrome (CRS) describes the progressive pathology and interactions that develop upon heart and kidney failure. The definition of CRS is not firmly established and has evolved gradually during the last decade. The main clinical challenges associated with CRS are the lack of tools for early disease diagnosis and the inability to predict the development of cardiorenal pathophysiology. Currently several biomarkers have been proposed for improving CRS patient management. However, validation studies are needed to implement these initial findings to the clinical setting. Areas covered: In this review the database PubMed was used for a literature search on the definition and classification of CRS as well as biomarkers for CRS diagnosis and prognosis. Expert opinion: A universally acceptable classification system for CRS is not available. Thus, acquiring mechanistic insights relative to the pathophysiology of the disease is challenging. Reported biomarkers include well-established markers for heart/renal dysfunction and inflammation. Some proteins expressed in both organs have also been associated with CRS, yet their link to disease pathophysiology and organ cross-talk is missing. Establishing the link between deregulated molecular pathways and CRS phenotypes is required to define biological relevance of existing findings and ultimately biology-driven markers and targets.

MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4.

Cardiovascular events are the leading cause of death in patients with chronic kidney disease (CKD), although the pathological mechanisms are poorly understood. Here we longitudinally characterized left ventricle pathology in a 5/6 nephrectomy rat model of CKD and identify novel molecular mediators. Next-generation sequencing of left ventricle mRNA and microRNA (miRNA) was performed at physiologically distinct points in disease progression, identifying alterations in genes in numerous immune, lipid metabolism, and inflammatory pathways, as well as several miRNAs. MiRNA miR-21-5p was increased in our dataset and has been reported to regulate many identified pathways. Suppression of miR-21-5p protected rats with 5/6 nephrectomy from developing left ventricle hypertrophy and improved left ventricle function. Next-generation mRNA sequencing revealed that miR-21-5p suppression altered gene expression in peroxisome proliferator-activated receptor alpha (PPARα) regulated pathways in the left ventricle. PPARα, a miR-21-5p target, is the primary PPAR isoform in the heart, importantly involved in regulating fatty acid metabolism. Therapeutic delivery of low-dose PPARα agonist (clofibrate) to rats with 5/6 nephrectomy improved cardiac function and prevented left ventricle dilation. Thus, comprehensive characterization of left ventricle molecular changes highlights the involvement of numerous signaling pathways not previously explored in CKD models and identified PPARα as a potential therapeutic target for CKD-related cardiac dysfunction.

Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology.

Heart failure (HF) secondary to myocardial infarction (MI) is linked to kidney complications that comprise cellular, structural, functional, and survival indicators. However, HF research is focused on left ventricular (LV) pathology. Here, we determined comprehensive functional analysis of the LV using echocardiography in transition from acute heart failure (AHF) to progressive chronic heart failure (CHF) pathology and developed a histological compendium of the cardiosplenic and cardiorenal networks in pathological remodeling. In surgically induced MI using permanent coronary ligation, the LV dysfunction is pronounced, with myocardium necrosis, wall thinning, and 20-30% LV rupture events that indicated AHF and CHF pathological remodeling in C57BL/6 male mice (2-4 mo old, n = 50). Temporal LV function analysis indicated that fractional shortening and strain are reduced from day 1 to day 5 in AHF and sustained to advance to CHF from day 28 to day 56 compared with naïve control mice ( n = 6). During the transition of AHF ( day 1 to day 5) to advanced CHF ( day 28 to day 56), histological and cellular changes in the spleen were definite, with bimodal inflammatory responses in kidney inflammatory biomarkers. Likewise, there was a unidirectional, progressive, and irreversible deposition of compact collagen in the LV along with dynamic changes in the cardiosplenic and cardiorenal networks post-MI. The renal histology and injury markers suggested that cardiac injury triggers irreversible dysregulation that actively alters the cardiosplenic and cardiorenal networks. In summary, the novel strategies or pathways that modulate comprehensive cardiosplenic and cardiorenal networks in AHF and CHF would be effective approaches to study either cardiac repair or cardiac pathology. NEW & NOTEWORTHY The present compendium shows irreversible ventricular dysfunction as assessed by temporal echocardiography while histological and structural measurements of the spleen and kidney added a novel direction to study cardiosplenic and cardiorenal networks in heart failure pathology. Therefore, the consideration of systems biology and integrative approach is essential to develop novel treatments.

Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress.

BACKGROUND/AIMS: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. METHODS: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. RESULTS: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-ß expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. CONCLUSIONS: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.

Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome.

BACKGROUND/AIMS: Chronic heart failure (HF) disrupts normal kidney function and leads to cardiorenal syndrome that further promotes HF progression. To identify potential participants in HF-related injury, we analyzed kidney proteome in an established HF model. METHODS: HF was induced by chronic volume overload in male HanSD rats using aorto-caval fistula. After 21 weeks, cardiac and renal functions (in-situ kidney study) and renal proteomics were studied in sham-operated (controls) and HF rats, using iTRAQ labeling and LC-MS with Orbitrap Fusion, leading to identification and quantification of almost 4000 proteins. RESULTS: Compared to controls, HF rats had cardiac hypertrophy, systemic and pulmonary congestion. Kidneys of HF rats had reduced renal blood flow, sodium excretion and urine production. While glomerular filtration rate, serum cystatin C and creatinine were still normal compared to controls, HF kidneys showed albuminuria and markedly increased tissue angiotensin-II levels (5-fold). HF kidneys (versus controls) displayed differential expression (˃1.5-fold) of 67 proteins. The most upregulated were angiotensin-converting enzyme (ACE, ˃20-fold), advanced glycosylation product-specific receptor (RAGE, 14-fold), periostin (6.8-fold), caveolin-1 (4.5-fold) and other proteins implicated in endothelial function (vWF, cavins 1-3, T-kininogen 2), proinflammatory ECM activation (MFAP4, collagen-VI, galectin-3, FHL-1, calponin) and proteins involved in glomerular filtration membrane integrity (CLIC5, ZO-1). Carboxylesterase-1D (CES1D), an enzyme that converts ACE inhibitors or sacubitril into active drugs, was also upregulated in HF kidneys. CONCLUSION: Chronic HF leads to latent kidney injury, associated with deep changes in kidney protein composition. These alterations may act in concert with intrarenal renin-angiotensin system activation and may serve as markers and/or targets to tackle cardiorenal syndrome.

Qiliqiangxin Protects against Renal Injury in Rat with Cardiorenal Syndrome Type I through Regulating the Inflammatory and Oxidative Stress Signaling.

Cardiorenal syndrome (CRS) is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. CRS remains a major global health problem. Qiliqiangxin (QLQX) is a traditional Chinese herbs medication, which can improve cardiac function, urine volume, and subjective symptoms in patients with chronic heart failure. In the present study, we aim to investigate the role of QLQX in the treatment of CRS type I and the possible mechanism through establishment of a rat model of myocardial infarction. Rats in CRS-Q group were orally treated with QLQX daily for 2 weeks or 4 weeks, while in sham group and CRS-C group were treated with saline at the same time. Enzyme-linked immunosorbent assay (ELISA) analysis showed that QLQX significantly reduced the levels of angiotensin II (AngII), brain natriuretic peptides (BNP), creatinine (CRE), cystatin C (CysC), tumor necrosis factor (TNF)-α, interleukin (IL)-6, microalbuminuria (MAU), and neutrophil gelatinase-associated lipocalin (NGAL) in plasma induced by myocardial infarction. Western blot analysis showed that QLQX significantly reduced the expressions of AngII, non-phagocytic cell oxidase (NOX)2, and B-cell lymphoma (Bcl)2 associated X protein (Bax), and increased the expressions of Bcl2 and Angiotensin II Type 1 receptor (ATR) in the kidney as compared with the CRS-C group. Fluorescence microscopy showed that the content of reactive oxygen species (ROS) was significantly reduced in the kidney as compared with the CRS-C group. We also examined the apoptosis level in kidney by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and the result showed that QLQX significantly reduced the apoptosis level in kidney induced by myocardial infarction. Taken together, we suggest that QLQX may be a potentially effective drug for the treatment of CRS by regulating inflammatory/oxidative stress signaling.

Targeting GPCR-Gßγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.

The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gßγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gßγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gßγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gßγ-GRK2 interactions. Further, we explore the potential of GPCR-Gßγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.

Biochemistry, Therapeutics, and Biomarker Implications of Neprilysin in Cardiorenal Disease.

BACKGROUND: Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology. Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3'-5' cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized. CONTENT: The biological functions of NEP and NPs are discussed. Enhancing NPs through NEP inhibition combined with renin-angiotensin-aldosterone system (RAAS) antagonism has proved to be successful in HF treatment, although future surveillance studies will be required. Direct NP enhancement through peptide delivery may have fewer potentially hazardous effects compared to NEP inhibition. Strategies of combined inhibition on NEP with other cardiorenal pathophysiological pathways are promising. Finally, monitoring BNP/NT-proBNP/cGMP concentrations during NEP inhibition treatment may provide supplemental benefits to conventional biomarkers, and the identification of soluble NEP as a novel biomarker for HF needs further investigation. SUMMARY: In this review, the biology of NEP is summarized, with a focus on NP regulation. The degradation of NPs by NEP provides the rationale for NEP inhibition as a strategy for cardiorenal disease treatment. We also describe the current therapeutic strategies of NEP inhibition and NP therapeutics in cardiorenal diseases. Moreover, the discovery of its circulating form, soluble NEP, as a biomarker is also discussed.