Bioinformatics analysis of the microRNA genes associated with type 2 cardiorenal syndrome.

BACKGROUND: MicroRNAs (miRNAs) are important regulatory factors in the normal developmental stages of the heart and kidney. However, it is currently unclear how miRNA is expressed in type 2 cardiorenal syndrome (CRS). This study aimed to detect the differential expression of miRNAs and to clarify the main enrichment pathways of differentially expressed miRNA target genes in type 2 CRS. METHODS: Five cases of healthy control (Group 1), eight of chronic heart failure (CHF, Group 2) and seven of type 2 CRS (Group 3) were enrolled, respectively. Total RNA was extracted from the peripheral blood of each group. To predict the miRNA target genes and biological signalling pathways closely related to type 2 CRS, the Agilent miRNA microarray platform was used for miRNA profiling and bioinformatics analysis of the isolated total RNA samples. RESULTS: After the microarray analysis was done to screen for differentially expressed circulating miRNAs among the three different groups of samples, the target genes and bioinformatic pathways of the differential miRNAs were predicted. A total of 38 differential miRNAs (15 up- and 23 down-regulated) were found in Group 3 compared with Group 1, and a total of 42 differential miRNAs (11 up- and 31 down-regulated) were found in Group 3 compared to Group 2. According to the Gene Ontology (GO) function and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, the top 10 lists of molecular functions, cellular composition and biological processes, and the top 30 signalling pathways of predicted gene targets of the differentially expressed miRNAs were discriminated among the three groups. CONCLUSION: Between the patients with CHF and type 2 CRS, miRNAs were differentially expressed. Prediction of target genes of differentially expressed miRNAs and the use of GO function and KEGG pathway analysis may reveal the molecular mechanisms of CRS. Circulating miRNAs may contribute to the diagnosis of CRS, and further and larger studies are needed to enhance the robustness of our findings.

CircRNA-mediated pathology: a new preliminary insight into the mechanism of type II cardio-renal syndrome.

AIM: The aim of this research was to investigate the expression of peripheral blood circular RNA (circRNA) in patients with type II cardio-renal syndrome, uncover the potential function and possible mechanisms mediated by circRNAs, and ultimately provide gene target support for the treatment of type II cardio-renal syndrome. METHODS: CircRNAs in the peripheral blood from five healthy individuals and 20 type II cardio-renal syndrome patients were collected for micro-array analysis. Another cohort study consisting of 12 normal cases and 15 type II cardiorenal syndrome patients was conducted to verify the chosen circRNA by quantitative real-time polymerase chain reaction. RESULTS: A total of 2 884 circRNAs were found to be differentially expressed in the group of patients with type II cardio-renal syndrome. Of these, 1 989 were upregulated and 895 were downregulated. One circRNA was then selected as a candidate biomarker and further validated in the second cohort. CONCLUSIONS: Differentially expressed mRNAs between patients with type II cardio-renal syndrome and healthy controls were enriched in two pathways, including haematopoietic cell lineage and cell adhesion molecules. CircRNA-mediated pathology is indispensable and plays an important role in the progress of type II cardio-renal syndrome. More importantly, hsa_cir_0001763 may be an important character in circRNA-mediated pathology.

Identification and external validation of the hub genes associated with cardiorenal syndrome through time-series and network analyses.

Cardiorenal syndrome (CRS), defined as acute or chronic damage to the heart or kidney triggering impairment of another organ, has a poor prognosis. However, the molecular mechanisms underlying CRS remain largely unknown. The RNA-sequencing data of the left ventricle tissue isolated from the sham-operated and CRS model rats at different time points were downloaded from the Gene Expression Omnibus (GEO) database. Genomic differences, protein-protein interaction networks, and short time-series analyses, revealed fibronectin 1 (FN1) and periostin (POSTN) as hub genes associated with CRS progression. The transcriptome sequencing data of humans obtained from the GEO revealed that FN1 and POSTN were both significantly associated with many different heart and kidney diseases. Peripheral blood samples from 20 control and 20 CRS patients were collected from the local hospital, and the gene expression levels of FN1 and POSTN were detected by real-time quantitative polymerase chain reaction. FN1 (area under the curve [AUC] = 0.807) and POSTN (AUC = 0.767) could distinguish CRS in the local cohort with high efficacy and were positively correlated with renal and heart damage markers, such as left ventricular ejection fraction. To improve the diagnostic ability, diagnosis models comprising FN1 and POSTN were constructed by logistic regression (F-Score = 0.718), classification tree (F-Score = 0.812), and random forest (F-Score = 1.000). Overall, the transcriptome data of CRS rat models were systematically analyzed, revealing that FN1 and POSTN were hub genes, which were validated in different public datasets and the local cohort.

Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study.

BACKGROUND: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. METHODS AND RESULTS: This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. CONCLUSION: Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.

Heat Shock Proteins: Connectors between Heart and Kidney.

Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. The heat shock proteins (HSPs), are a family of proteins that have been linked to different cellular functions, being activated under conditions of cellular stress, not only imposed by thermal variation but also toxins, radiation, infectious agents, hypoxia, etc. Regarding pathological situations as seen in cardiorenal syndrome (CRS), HSPs have been shown to be important mediators involved in the control of gene transcription and intracellular signaling, in addition to be an important connector with the immune system. CRS is classified as acute or chronic and according to the first organ to suffer the injury, which can be the heart (CRS type 1 and type 2), kidneys (CRS type 3 and 4) or both (CRS type 5). In all types of CRS, the immune system, redox balance, mitochondrial dysfunction, and tissue remodeling have been the subject of numerous studies in the literature in order to elucidate mechanisms and propose new therapeutic strategies. In this sense, HSPs have been targeted by researchers as important connectors between kidney and heart. Thus, the present review has a focus to present the state of the art regarding the role of HSPs in the pathophysiology of cardiac and renal alterations, as well their role in the kidney-heart axis.

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.

Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. Deficiency of FGF23 causes growth retardation and shortens the lifespan, but it is unclear whether excess FGF23 is detrimental in CRS. This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis. A mouse model of CRS was created by surgical myocardial infarction for 12 weeks. CRS mice showed a significant increase of circulatory and renal FGF23 protein levels, as well as an upregulation of p-GSK, active-ß-catenin, TGF-ß, collagen I and vimentin, a downregulation of renal Klotho expression and induction of cardiorenal dysfunction and cardiorenal fibrosis. These changes were enhanced by cardiac overexpression of FGF23 and attenuated by FGF receptor blocker PD173074 or ß-catenin blocker IGC001. In fibroblasts (NRK-49F), expression of FGFR4 rather than Klotho was detected. Recombinant FGF23 upregulated the expression of p-GSK, active-ß-catenin, TGF-ß, collagen I and vimentin proteins. These changes were attenuated by FGFR4 blockade with BLU9931 or ß-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/ß-catenin signaling pathway.

RNA interactions in right ventricular dysfunction induced type II cardiorenal syndrome.

Right ventricular (RV) dysfunction induced type II cardiorenal syndrome (CRS) has a high mortality rate, but little attention has been paid to this disease, and its unique molecular characteristics remain unclear. This study aims to investigate the transcriptomic expression profile in this disease and identify key RNA pairs that regulate related molecular signaling networks. We established an RV dysfunction-induced type II CRS mouse model by pulmonary artery constriction (PAC). PAC mice developed severe RV hypertrophy and fibrosis; renal atrophy and dysfunction with elevated creatinine were subsequently observed. Expression profiles in RV and kidney tissues were obtained by whole transcriptome sequencing, revealing a total of 741 and 86 differentially expressed (DE) mRNAs, 159 and 29 DEmiRNAs and 233 and 104 DEcircRNAs between RV and kidney tissue, respectively. Competing endogenous RNA (ceRNA) networks were established. A significant alteration in proliferative, fibrotic and metabolic pathways was found based on GO and KEGG analyses, and the network revealed key ceRNA pairs, such as novel_circ_002631/miR-181a-5p/Creb1 and novel_circ_002631/miR-33-y/Kpan6. These findings indicate that significantly dysregulated pathways in RV dysfunction induced type II CRS include Ras, PI3K/Akt, cGMP-PKG pathways, and thyroid metabolic pathways. These ceRNA pairs can be considered potential targets for the treatment of type II CRS.

Caspase-1 as Molecular Key in Cardiac Remodeling during Cardiorenal Syndrome Type 3 in the Murine Model.

BACKGROUND: Renal ischemia/reperfusion induces a systemic inflammatory response that is directly related to the development of cardiac hypertrophy due to cardiorenal syndrome type 3. Classic inflammatory pathways have been extensively investigated in cardiovascular diseases, including the participation of inflammasome in caspase-1-dependent IL-1ß cleavage. OBJECTIVE: In this study, we aimed to understand how lack of caspase-1 would impact the hypertrophic and apoptotic response in the heart after renal ischemia/reperfusion. METHODS: Wildtype and caspase-1 knockout animals were submitted to a renal ischemia/reperfusion protocol. Briefly, left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 15 days. Gene expression was analysed by Real-Time PCR. Caspase activity was also evaluated. RESULTS: Lack of caspase-1 led to a more pronounced cardiac hypertrophy in mice subjected to renal ischemia-reperfusion. Such hypertrophic process was accompanied by increased activity of caspase3/7 and 9, indicating apoptosis initiation in an IL-1ß- independent manner. CONCLUSION: Our data corroborate important findings on the role of caspase-1 in the development of cardiac hypertrophy and remodeling.

SIRT1 gene polymorphisms are associated with nondiabetic type 1 cardiorenal syndrome.

Type 1 cardiorenal syndrome (CRS1) is characterized by acute cardiac disease (e.g., acute heart failure [AHF]), leading to acute kidney injury. Sirtuin 1 (SIRT1), an NAD+ -dependent deacylase, has been found to be associated with CRS1. To confirm whether a correlation exists between SIRT1 variants and the risk of CRS1, the association between the prevalence of CRS1 and single-nucleotide polymorphisms (SNPs) within the SIRT1 gene was investigated in AHF patients. A total of 316 Chinese AHF participants (158 patients with CRS1 and 158 age- and sex-matched controls) were recruited for the present observational study to investigate the association between nine common SIRT1 SNPs (i.e., rs7895833 G > A, rs10509291 T > A, rs3740051 A > G, rs932658 A > C, rs33957861 C > T, rs7069102 C > G, rs2273773 T > C, rs3818292 A > G, and rs1467568 A > G) and the susceptibility to CRS1. Significant differences in genotype distribution between the control and CRS1 groups were found for rs7895833 and rs1467568. After applying a Bonferroni adjustment, the A allele of rs7895833 was still found to be protective (p = 0.001; odds ratio [OR] = 0.77) against CRS1 in this study population. The AA genotype of rs7895833 and the GA genotype of rs1467568 were associated with a significantly reduced risk of CRS1 (OR = 0.23 and 0.49, respectively). rs7895833 and rs1467568 were further analyzed as a haplotype, and the GA haplotype (rs7895833-rs1467568) exhibited a significant association with CRS1 (p = 0.008), while the AA haplotype showed a significant protective effect (p = 0.022). Our study showed that SIRT1 rs7895833 and rs1467568 polymorphisms had a significant effect on the risk of developing CRS1 in a population in China.

The therapeutic impact of entresto on protecting against cardiorenal syndrome-associated renal damage in rats on high protein diet.

BACKGROUND: This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (HPD). METHODS AND RESULTS: Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + HPD), Group 2 (CRS + HPD) and Group 3 [CRS + HPD + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e., DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e., beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001). CONCLUSION: Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage.

Multi-Omics Approach: New Potential Key Mechanisms Implicated in Cardiorenal Syndromes.

Cardiorenal syndromes (CRS) include a scenario of clinical interactions characterized by the heart and kidney dysfunction. The crosstalk between cardiac and renal systems is clearly evidenced but not completely understood. Multi-factorial mechanisms leading to CRS do not involve only hemodynamic parameters. In fact, in recent works on organ crosstalk endothelial injury, the alteration of normal immunologic balance, cell death, inflammatory cascades, cell adhesion molecules, cytokine and chemokine overexpression, neutrophil migration, leukocyte trafficking, caspase-mediated induction of apoptotic mechanisms and oxidative stress has been demonstrated to induce distant organ dysfunction. Furthermore, new alternative mechanisms using the multi-omics approach may be implicated in the pathogenesis of cardiorenal crosstalk. The study of "omics" modifications in the setting of cardiovascular and renal disease represents an emerging area of research. Over the last years, indeed, many studies have elucidated the exact mechanisms involved in gene expression and regulation, cellular communication and organ crosstalk. In this review, we analyze epigenetics, gene expression, small non-coding RNAs, extracellular vesicles, proteomics, and metabolomics in the setting of CRS.

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.

Epigenetics: a potential key mechanism involved in the pathogenesis of cardiorenal syndromes.

Epigenetics is defined as the heritable changes in gene expression patterns which are not directly encoded by modifications in the nucleotide DNA sequence of the genome, including higher order chromatin organization, DNA methylation, cytosine modifications, covalent histone tail modifications, and short non-coding RNA molecules. Recently, much attention has been paid to the role and the function of epigenetics and epimutations in the cellular and subcellular pathways and in the regulation of genes in the setting of both kidney and cardiovascular disease. Indeed, deregulation of histone alterations has been highlighted in a large spectrum of renal and cardiac disease, including chronic and acute renal injury, renal and cardiac fibrosis, cardiac hypertrophy and failure, kidney congenital anomalies, renal hypoxia, and diabetic renal complications. Nevertheless, the role of epigenetics in the pathogenesis and pathophysiology of cardiorenal syndromes is currently underexplored. Given the significant clinical relevance of heart-kidney crosstalk, efforts in the research for new action mechanisms concurrently operating in both pathologies are thus of maximum interest. This review focuses on epigenetic mechanisms involved in heart and kidney disease, and their possible role in the setting of cardiorenal syndromes.

Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy.

The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant α-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 vs. wild type 0.65 ± 0.16 mg/dl, P < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ml, P < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the Ren1 gene, marked overexpression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice vs. 2.01 ± 0.58 mg/dl in wild type, P < 0.05), urine NGAL (9,198.79 ± 3,799.52 in transgenic mice vs. 3,252.94 ± 2,420.36 ng/ml in wild type, P < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, P < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, P < 0.05), and TdT-mediated dUTP nick-end labeling (TUNEL)-positive nuclei (10.1 ± 2.1 in the transgenic group vs. 5.7 ± 1.6 per 100 cells counted in wild type, P < 0.01). Our findings indicate functional renal impairment, urinary biomarker elevations, and induction of renin gene and protein expression in the kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury.

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

Molecular and Genetic Mechanisms Involved in the Pathogenesis of Cardiorenal Cross Talk.

The term 'cardiorenal syndrome' (CRS) encloses a scenario of clinical interactions in which cardiac and renal dysfunctions coexist. The cross talk between the heart and the kidney is clearly evidenced but not fully understood. Indeed, different factors have been shown to be involved in the pathogenesis of CRS, such as systemic inflammation, oxidative stress, apoptosis and immune dysregulation. Recently, considerable attention has been paid to the role of new alternative mechanisms which may be implicated in the pathogenesis of cardiorenal cross talk. In this review, we will focus on epigenetics, prenatal programming, small noncoding RNAs and extracellular vesicles, aiming to elucidate their possible role in heart and kidney diseases.

Fisiopatología de la insuficiencia cardiaca aguda: un mundo por conocer / Pathophysiology of acute heart failure: a world to know

La comprensión de los mecanismos fisiopatológicos de la insuficiencia cardiaca (IC) ha evolucionado mucho en los últimos años, pasando de una visión meramente hemodinámica a un concepto de afectación sistémica y multifactorial en la que interaccionan y se concatenan múltiples mecanismos, con efectos más allá del propio corazón, en órganos de vital importancia como el riñón, el hígado o el pulmón. A pesar de lo anterior, la fisiopatología de la IC aguda presenta todavía aspectos que escapan a una profunda comprensión. La sobrecarga hemodinámica, la congestión venosa, los sistemas neurohormonales, los péptidos natriuréticos, la inflamación, el estrés oxidativo y su repercusión sobre el remodelado cardiaco y vascular se consideran hoy actores principales en la IC aguda. Partiendo del concepto de IC aguda, en esta revisión se actualizan los distintos mecanismos implicados en la misma (AU)

Our understanding of the pathophysiological mechanisms of heart failure (HF) has changed considerably in recent years, progressing from a merely haemodynamic viewpoint to a concept of systemic and multifactorial involvement in which numerous mechanisms interact and concatenate. The effects of these mechanisms go beyond the heart itself, to other organs of vital importance such as the kidneys, liver and lungs. Despite this, the pathophysiology of acute HF still has aspects that elude our deeper understanding. Haemodynamic overload, venous congestion, neurohormonal systems, natriuretic peptides, inflammation, oxidative stress and its repercussion on cardiac and vascular remodelling are currently considered the main players in acute HF. Starting with the concept of acute HF, this review provides updates on the various mechanisms involved in this disease (AU)

Molecular models of the cardiorenal syndrome.

Molecular profiling techniques have provided extensive sets of molecular features characterizing clinical phenotypes, but further extrapolation to mechanistic molecular models of disease pathophysiology faces major challenges. Here, we describe a computational procedure for delineating molecular disease models utilizing omics profiles, and exemplify the methodology on aspects of the cardiorenal syndrome describing the clinical association of declining kidney function and increased cardiovascular event rates. Individual molecular features as well as selected molecular processes were identified as linking cardiovascular and renal pathology as a combination of cross-organ mediators and common pathophysiology. The molecular characterization of the disease presents as a set of molecular processes together with their interactions, composing a molecular disease model of the cardiorenal syndrome. Integrating omics profiles describing aspects of cardiovascular disease and respective profiles for advanced chronic kidney disease on molecular interaction networks, computation of disease term-specific subgraphs, and complemented by subgraph segmentation allowed delineation of disease term-specific molecular models, at their intersection providing contributors to cardiorenal pathology. Building such molecular disease models allows in a generic way to integrate multi-omics sources for generating comprehensive sets of molecular processes, on such basis providing rationale for biomarker panel selection for further characterizing clinical phenotypes.

Molecular and metabolic mechanisms of cardiac dysfunction in diabetes.

Diabetes mellitus type 2 (T2DM) is a widespread chronic medical condition with prevalence bordering on the verge of an epidemic. It is of great concern that cardiovascular disease is more common in patients with diabetes than the non-diabetic population. While hypertensive and ischemic heart disease is more common in diabetic patients, there is another type of heart disease in diabetes that is not associated with hypertension or coronary artery disease. This muscle functional disorder is termed "diabetic cardiomyopathy". Diastolic dysfunction characterized by impaired diastolic relaxation time and reduced contractility precedes systolic dysfunction and is the main pathogenic hallmark of this condition. Even though the pathogenesis of "diabetic cardiomyopathy" is still controversial, impaired cardiac insulin sensitivity and metabolic overload are emerging as major molecular and metabolic mechanisms for cardiac dysfunction. Systemic insulin resistance, hyperinsulinemia, dysregulation of adipokine secretion, increases in circulating levels of inflammatory mediators, aberrant activation of renin angiotensin aldosterone system (RAAS), and increased oxidative stress contribute dysregulated insulin and metabolic signaling in the heart and development of diastolic dysfunction. In addition, maladaptive calcium homeostasis and endothelial cell dysregulation endoplasmic reticular stress play a potential role in cardiomyocyte fibrosis/diastolic dysfunction. In this review, we will focus on emerging molecular and metabolic pathways underlying cardiac dysfunction in diabetes. Elucidation of these mechanisms should provide a better understanding of the various cardiac abnormalities associated with diastolic dysfunction and its progression to systolic dysfunction and heart failure.