Downregulation of Tnf-α and Cat Expression in a Wistar Rat Diabetic Model during Diabetes Onset.

INTRODUCTION: Diabetes Mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia and/or insulin resistance. If left uncontrolled, it can lead to a combination of cardiac and renal alterations known as cardiorenal syndrome. Additionally, oxidative stress and inflammation contribute to tissue damage, thereby reducing the life expectancy of individuals with diabetes. AIM: The aim of this study was to identify early molecular markers associated with cardiorenal syndrome, oxidative stress, and inflammation, and to investigate their correlation with the duration of exposure to DM. METHODS: An experimental DM model was employed using Wistar rats. The rats were divided into four groups: diabetic rats at 7 days (DM7), diabetic rats at 30 days (DM30), control sham at 7 days (CS7), and control sham at 30 days (CS30). Blood and brain tissue from the brainstem region were collected at 7 and 30 days after confirming DM induction. Gene expression analysis of Bnp, Anp, Cat, Gpx, Sod, Tnf-α, and Il-6 was performed. RESULTS: The analysis revealed lower expression values of Cat in the brainstem tissue of the DM7 group compared to the NDS7 group. Moreover, diabetic animals exhibited statistically lower levels of Tnf-α in their peripheral blood compared to the control animals. CONCLUSION: This study concluded that DM alters the oxidative balance in the brainstem after 7 days of DM induction, resulting in lower Cat expression levels. Although some genes did not show statistical differences after 30 days of DM induction, other genes exhibited no expression values, indicating possible gene silencing. The study identified an imbalance in the studied pathways and concluded that the organism undergoes a compensatory state in response to the initial metabolic alterations caused by DM.

Heart Failure With Reduced Ejection Fraction in a Patient With Erdheim-Chester Disease on Dabrafenib.

A 54-year-old woman with a diagnosis of Erdheim-Chester disease under therapy with dabrafenib presents with clinical signs of heart failure. After discontinuing the offending medication and initiating guideline-directed medical therapy for heart failure with reduced ejection fraction, the clinical picture improved.

Cholinergic Stimulation Exerts Cardioprotective Effects and Alleviates Renal Inflammatory Responses after Acute Myocardial Infarction in Spontaneous Hypertensive Rats (SHRs).

BACKGROUND: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). METHODS: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. RESULTS: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury. CONCLUSIONS: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

Effect on Kidney Function Recovery Guiding Decongestion with VExUS in Patients with Cardiorenal Syndrome 1: A Randomized Control Trial.

INTRODUCTION: In cardiorenal syndrome type 1 (CRS1), vascular congestion is central to the pathophysiology of heart failure and thus a key target for management. The venous evaluation by ultrasound (VExUS) system could guide decongestion effectively and thereby improve outcomes. METHODS: In this randomized clinical trial, patients with CRS1 (i.e., increase in creatinine ≥0.3 mg/dL) were randomized to guide decongestion with VExUS compared to usual clinical evaluation. The primary endpoint was to assess kidney function recovery (KFR), and the key secondary endpoint was decongestion evaluated by physical examination and changes in brain natriuretic peptide (BNP) and CA-125. Exploratory endpoints included days of hospitalization and mortality. RESULTS: From March 2022 to February 2023, a total of 140 patients were randomized 1:1 (70 in the VExUS and 70 in the control group). KFR was not statistically different between groups. However, VExUS improved more than twice the odds to achieve decongestion (odds ratio [OR]: 2.6, 95% CI: 1.9-3.0, p = 0.01) and the odds to reach a decrease of BNP >30% (OR: 2.4, 95% CI: 1.3-4.1, p = 0.01). The survival at 90 days, recongestion, and CA-125 were similar between groups. CONCLUSION: In patients with CRS1, we observed that VExUS-guided decongestion did not improve the probability of KFR but improved the odds to achieve decongestion.

Síndrome cardiorrenal tipo 4 en paciente revascularizado percutáneamente

Introducción: el síndrome cardiorrenal es una patología dada por la disfunción en la interdependencia de estos órganos por interacciones bidireccionales (agudas o crónicas), los cuales pueden afectar indistintamente la función renal o ventricular. Objetivo: presentar y justificar la enfermedad renal crónica como desencadenante de cuadros congestivos por falla cardiaca de novo. Presentación del caso: se reporta el caso de un paciente masculino de 69 años revascularizado percutáneamente hace tres años con múltiples comorbilidades que ingresa en el contexto de una falla cardiaca de novo, secundaria a su enfermedad renal crónica estadio V de base, en manejo con hemodiálisis y en quien se descartó enfermedad coronaria aguda y miocardiopatía infiltrativa. Se logró estabilizar la injuria renal y cardiaca dando egreso y continuando manejo ambulatorio de sus patologías, al llevar un control adecuado de las mismas con Nefrología y Cardiología. Discusión y conclusión: la enfermedad cardiovascular generada por antecedentes renales tiene una gran repercusión en la función ventricular izquierda, causando hipertrofia, lo que lleva a una congestión con posterior sobrecarga debido a la caída del filtrado glomerular y que resulta en la disminución de la fracción de eyección. La enfermedad renal crónica predispone a alteraciones en la función cardiaca, lo que aumenta el riesgo cardiovascular.

Background: Cardiorenal syndrome is a pathology caused by dysfunction in the interdependence of these organs due to bidirectional interactions (acute or chronic), which can affect either renal or ventricular function. Purpose: To present and justify chronic kidney disease as a trigger of congestive conditions due to de novo heart failure. Case presentation: We report the case of a 69-year-old male patient percutaneously revascularized 3 years ago with multiple comorbidities who was admitted in the context of de novo heart failure secondary to his stage V chronic kidney disease on hemodialysis, in whom acute coronary artery disease and infiltrative cardiomyopathy were ruled out. The renal and cardiac injury was stabilized and the patient was discharged and continued outpatient management of his pathologies with adequate control of the same with nephrology and cardiology. Discussion and conclusion: Cardiovascular disease generated by renal history has great repercussion in left ventricular function causing hypertrophy that leads to congestion with subsequent overload due to the fall of glomerular filtration resulting in a decrease of the ejection fraction. Chronic kidney disease predisposes to alterations in cardiac function increasing cardiovascular risk.

Mitochondrial Impairment: A Link for Inflammatory Responses Activation in the Cardiorenal Syndrome Type 4.

Cardiorenal syndrome type 4 (CRS type 4) occurs when chronic kidney disease (CKD) leads to cardiovascular damage, resulting in high morbidity and mortality rates. Mitochondria, vital organelles responsible for essential cellular functions, can become dysfunctional in CKD. This dysfunction can trigger inflammatory responses in distant organs by releasing Damage-associated molecular patterns (DAMPs). These DAMPs are recognized by immune receptors within cells, including Toll-like receptors (TLR) like TLR2, TLR4, and TLR9, the nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome, and the cyclic guanosine monophosphate (cGMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (cGAS-STING) pathway. Activation of these immune receptors leads to the increased expression of cytokines and chemokines. Excessive chemokine stimulation results in the recruitment of inflammatory cells into tissues, causing chronic damage. Experimental studies have demonstrated that chemokines are upregulated in the heart during CKD, contributing to CRS type 4. Conversely, chemokine inhibitors have been shown to reduce chronic inflammation and prevent cardiorenal impairment. However, the molecular connection between mitochondrial DAMPs and inflammatory pathways responsible for chemokine overactivation in CRS type 4 has not been explored. In this review, we delve into mechanistic insights and discuss how various mitochondrial DAMPs released by the kidney during CKD can activate TLRs, NLRP3, and cGAS-STING immune pathways in the heart. This activation leads to the upregulation of chemokines, ultimately culminating in the establishment of CRS type 4. Furthermore, we propose using chemokine inhibitors as potential strategies for preventing CRS type 4.

Diuretics and Ultrafiltration in Heart Failure.

Fluid overload is a risk factor for increased morbidity and mortality, especially in patients with heart disease. The treatment options are limited to diuretics and mechanical fluid removal using ultrafiltration or renal replacement therapy. This paper provides an overview of the challenges of managing fluid overload, outlines the risks and benefits of different pharmacological options and extracorporeal techniques, and provides guidance for clinical practice.

Progress and Challenges of Understanding Cardiorenal Syndrome Type 3.

The pathologies of the kidney and heart have instigated a large number of researchers around the world to try to better understand what the exact connectors responsible for the emergence and establishment of these diseases are. The classification of these pathologies into different types of cardiorenal syndromes (CRSs) over the last 15 years has greatly contributed to understanding pathophysiological and diagnostic aspects, as well as treatment strategies. However, with the advent of new technologies classified as "Omics", a new range of knowledge and new possibilities have opened up in order to effectively understand the intermediaries between the kidney-heart axis. The universe of micro-RNAs (miRNAs), epigenetic factors, and components present in extracellular vesicles (EVs) have been protagonists in studying different types of CRSs. Thus, the new challenge that is imposed is to select and link the large amount of information generated from the use of large-scale analysis techniques. The present review seeks to present some of the future perspectives related to understanding CRSs, with an emphasis on CRS type 3.

Consumo de Castanha-do-Brasil reduz o N-óxido de trimetilamina (TMAO) e a inflamação em um paciente com síndrome cardiorrenal: uma comunicação breve / Brazil nut consumption reduces trimethylamine-n-oxide (TMAO) and inflammation in a patient with cardiorenal syndrome: a brief communication

Introdução: A disbiose intestinal é uma característica comum na síndrome cardiorrenal e está associada ao aumento de toxinas urêmicas, como o N-óxido de trimetilamina (TMAO), que estão envolvidas com a inflamação e mortalidade cardiovascular. A castanha-do-Brasil (semente típica brasileira) possui propriedades anti-inflamatórias e antioxidantes, mas não há evidências dos seus efeitos na modulação da microbiota intestinal e redução de toxinas urêmicas. Objetivo: Avaliar o impacto do consumo de castanha-do-Brasil nos níveis de TMAO e marcadores de inflamação em um paciente com síndrome cardiorrenal. Métodos: Um paciente com doença arterial coronariana (66 anos e IMC, 26 kg/m2), estágio 3 da DRC (TFGe 36 mL/min), recebeu uma castanha-do-Brasil por dia durante três meses. Resultados: Os níveis plasmáticos de TMAO e a expressão de mRNA de NF-κB foram reduzidos e a atividade da glutationa peroxidase (GPx) aumentou após esta intervenção. Conclusão: A prescrição de castanha-do-Brasil pode ser uma estratégia promissora para mitigar as complicações relacionadas à síndrome cardiorrenal. Este caso apoia o conceito de "alimento como remédio" visando o fenótipo urêmico na síndrome cardiorrenal.

Introduction: Gut dysbiosis is a common feature in cardiorenal syndrome, and it is linked to increased uremic toxins, like trimethylamine-n-oxide (TMAO), which are involved with inflammation and cardiovascular mortality. Brazil nut (typical Brazilian seed) has anti-inflammatory and antioxidant properties, but there is no evidence of the effects of gut microbiota modulation and reduction of uremic toxins. Objective: To assess the impact of Brazil nut consumption on TMAO levels and inflammation markers in a patient with cardiorenal syndrome. Methods: Acoronary artery disease patient(66 years and BMI, 26 kg/m2),stage-3 of CKD (eGFR 36 mL/min), receivedone Brazil nut per day for three months. Results: TMAO plasma levels and NF-κB mRNA expression were reduced, and glutathione peroxidase (GPx) activity increased after this intervention. Conclusion: Brazil nut prescription may be a promising strategy to mitigate complications related tothe cardiorenal syndrome. This case supports the concept of "Food as medicine" targeting the uremic phenotype in cardiorenal syndrome.

El riñón en el trasplante cardíaco, relato de una travesía / The Kidney in Heart Transplantation, Tale of a Journey

RESUMEN La intención de esta actualización es destacar la relación que se establece entre el corazón y el riñón a lo largo de toda la travesía que implica un trasplante cardíaco. Frente al mismo, el sistema cardiovascular y el renal se comportan como compañeros de un viaje que, a veces, es difícil determinar cuándo comienza, y que los obliga a superar diferentes obstáculos, como los cambios hemodinámicos, la respuesta neurohumoral e inflamatoria, la injuria quirúrgica, la reacción inmunológica y la toxicidad medicamentosa. Esta relación puede verse como una aventura que indefectiblemente deben compartir. En este viaje trataremos de acompañar a ambos órganos, pero fijando la atención especialmente en el riñón, y describir las conexiones, mecanismos de protección y de perjuicio que se generan a lo largo del recorrido. En la travesía podemos reconocer respuestas solidarias, para sostener el equilibrio entre ambos sistemas, pero en ese intento de protección se producen daños colaterales.

ABSTRACT The aim of this update is to highlight the relationship between the heart and the kidney throughout the entire journey involved in heart transplantation. Faced with heart transplantation, the cardiovascular and renal systems behave as mates of a journey that, at times, is difficult to determine when it starts, and that forces them to overcome different obstacles, such as hemodynamic changes, neurohumoral and inflammatory response, surgical injury, immune reaction, and drug toxicity. This relationship can be seen as an adventure that they must inevitably share. We will try to accompany both organs in this journey, but paying special attention to the kidney, describing the associations and the protection and damage mechanisms that are generated throughout its course. In this journey we can recognize solidarity responses to maintain the balance between both systems, but in this attempt to protect, collateral injury occurs.

Unilateral Acute Renal Ischemia-Reperfusion Injury Induces Cardiac Dysfunction through Intracellular Calcium Mishandling.

BACKGROUND: Acute renal failure (ARF) following renal ischemia-reperfusion (I/R) injury is considered a relevant risk factor for cardiac damage, but the underlying mechanisms, particularly those triggered at cardiomyocyte level, are unknown. METHODS: We examined intracellular Ca2+ dynamics in adult ventricular cardiomyocytes isolated from C57BL/6 mice 7 or 15 days following unilateral renal I/R. RESULTS: After 7 days of I/R, the cell contraction was significantly lower in cardiomyocytes compared to sham-treated mice. It was accompanied by a significant decrease in both systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transients decay. Moreover, the incidence of pro-arrhythmic events, measured as the number of Ca2+ sparks, waves or automatic Ca2+ transients, was greater in cardiomyocytes from mice 7 days after I/R than from sham-treated mice. Ca2+ mishandling related to systolic Ca2+ transients and contraction were recovered to sham values 15 days after I/R, but Ca2+ sparks frequency and arrhythmic events remained elevated. CONCLUSIONS: Renal I/R injury causes a cardiomyocyte Ca2+ cycle dysfunction at medium (contraction-relaxation dysfunction) and long term (Ca2+ leak), after 7 and 15 days of renal reperfusion, respectively.

Cardiorenal syndrome: long road between kidney and heart.

Almost 200 years ago, the first evidence described by Robert Bright (1836) showed the strong interaction between the kidneys and heart and, since then, the scientific community has dedicated itself to better understanding the mechanisms involved in the kidney-heart relationship, known in recent decades as cardiorenal syndrome (CRS). This syndrome includes a wide clinical variety that affects the kidneys and heart, in an acute or chronic manner. Moreover, it is well established in the literature that the immune system, the sympathetic nervous system, the renin-angiotensin-aldosterone, and the oxidative stress actively play a strong role in the cellular and molecular processes present in CRS. More recently, uremic molecules and epigenetic factors have been also shown to be key mediators in the development of syndrome. The present review intends to present the state of the art regarding CRS and to show the paths known, until now, in the long road between the kidneys and heart.

How to interpret serum creatinine increases during decongestion.

During decongestion in acute decompensated heart failure (ADHF), it is common to observe elevations in serum creatinine (sCr) values due to vascular congestion, a mechanism that involves increased central venous pressure that has a negative impact on the nephron, promoting greater absorption of water and sodium, increased interstitial pressure in an encapsulated organ developing "renal tamponade" which is one of main physiopathological mechanism associated with impaired kidney function. For the treatment of this syndrome, it is recommended to use diuretics that generate a high urinary output and natriuresis to decongest the venous system, during this process the sCr values can rise, a phenomenon that may bother some cardiologist and nephrologist, since raise the suspicion of kidney damage that could worsen the prognosis of these patients. It is recommended that increases of up to 0.5 mg/dL from baseline are acceptable, but some patients have higher increases, and we believe that an arbitrary number would be impractical for everyone. These increases in sCr may be related to changes in glomerular hemodynamics and true hypovolemia associated with decongestion, but it is unlikely that they are due to structural injury or truly hypoperfusion and may even have a positive connotation if accompanied by an effective decongestion and be associated with a better prognosis in the medium to long term with fewer major cardiovascular and renal events. In this review, we give a comprehensive point of view on the interpretation of creatinine elevation during decongestion in patients with ADHF.

Cardiorenal syndrome: classification, pathophysiology, diagnosis and management. Literature review / Síndrome cardiorrenal: clasificación, fisiopatología, diagnóstico y tratamiento. Una revisión de las publicaciones médicas.

The cardiorenal syndrome is a complex entity in which a primary heart dysfunction causes kidney injury (Types 1 and 2) and vice versa (Types 3 and 4), being either acute or chronic events, or maybe the result of a systemic disease that involves both organs (Type 5). Approximately 49% of heart failure cases present some grade of kidney dysfunction, significantly increasing morbidity and mortality rates. Its pathogenesis involves a variety of hemodynamic, hormonal and immunological factors that in the majority of cases produce fluid overload; the diagnosis and treatment of such constitutes the disease's management basis. Currently, a clinical based diagnosis is insufficient and the use of biochemical markers, such as natriuretic peptides, or lung and heart ultrasound is required. These tools, along with urinary sodium levels, allow the evaluation of therapy effectiveness. The preferred initial decongestive strategy is based on a continuous infusion of a loop diuretic with a step-up dosing regimen, aiming for a minimal daily urine volume of 3 liters, with the possibility to sequentially add potassium sparing diuretics, thiazide diuretics and carbonic anhydrase inhibitors to reach the diuresis goal, leaving ultrafiltration as a last resource due to its higher rate of complications. Finally, evidence-based therapy should be given to improve quality of life, decrease mortality, and delay the deterioration of kidney and heart function over the long term.

El síndrome cardiorrenal es una entidad compleja en la que la disfunción primaria cardíaca produce daño renal (tipos 1 y 2) y viceversa (tipos 3 y 4) y los episodios pueden ser agudos o crónicos o bien efecto de una enfermedad sistémica que afecta a ambos órganos (tipo 5). Hasta 49% de los pacientes con insuficiencia cardíaca muestra algún grado de disfunción renal, lo que aumenta de manera significativa la morbilidad y mortalidad. Su patogenia incluye diversos factores hemodinámicos, hormonales e inmunológicos que en la mayor parte de los casos producen sobrecarga hídrica, y cuyo diagnóstico y tratamiento son la base de su atención. En la actualidad, el diagnóstico clínico es insuficiente y se requieren marcadores bioquímicos, como péptidos natriuréticos, o el uso de ultrasonido pulmonar y cardíaco; estas herramientas, junto con la medición del sodio urinario, también permiten vigilar la efectividad terapéutica. De modo inicial se prefieren las medidas descongestivas con diuréticos de asa en infusión continua a dosis escalonadas para alcanzar una diuresis mínima de 3 L por día, con la posibilidad de agregar diuréticos ahorradores de potasio, tiazidas e inhibidores de la anhidrasa carbónica de modo secuencial para alcanzar el objetivo; como último recurso se recurre a la ultrafiltración en virtud de su mayor tasa de complicaciones. Por último, se debe indicar tratamiento con base en la evidencia para mejorar la calidad de vida, reducir la mortalidad y retrasar el deterioro de la función renal y cardíaca a largo plazo.

Amlexanox Exhibits Cardioprotective Effects in 5/6 Nephrectomized Rats

Abstract Cardiorenal syndrome is a life-threatening condition. The aim of the current study was to determine the cardioprotective effects of amlexanox in 5/6 nephrectomized rats. Rats were randomly assigned to three groups: sham, 5/6 nephrectomized rats, and amlexanox-treated 5/6 nephrectomized group. Amlexanox (25 mg/kg/day, i.p.) administration was started just after surgery and continued for 10 weeks. After treatment, kidney function (serum creatinine and urea) and blood pressure (systolic and diastolic) were measured. Heart weight (normalized to tibial length) and fibrosis area percentage were measured. Serum brain natriuretic peptide (BNP, heart failure marker) and cardiac levels of ß1-adrenergic receptor (ß1AR), ß-arrestin-2, phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol (DAG), pS473 Akt (a survival marker), and caspase-3 activity (an apoptosis marker) were also measured. The 5/6 nephrectomy caused renal impairment, cardiac fibrosis, apoptosis, and heart failure indicated by down- regulation of cardiac ß1AR down-stream signals compared with those in the sham group. Interestingly, amlexanox significantly reduced all cardiopathological changes induced after 10 weeks of 5/6 nephrectomy. Amlexanox showed potent cardiac antifibrotic and antiapoptotic effects in 5/6 nephrectomized rats, which were associated with reduced heart failure. To our knowledge, this is the first study that addresses the potent in vivo cardioprotective effects of amlexanox

Extracellular Vesicles and Their Relationship with the Heart-Kidney Axis, Uremia and Peritoneal Dialysis.

Cardiorenal syndrome (CRS) is described as primary dysfunction in the heart culminating in renal injury or vice versa. CRS can be classified into five groups, and uremic toxin (UT) accumulation is observed in all types of CRS. Protein-bound uremic toxin (PBUT) accumulation is responsible for permanent damage to the renal tissue, and mainly occurs in CRS types 3 and 4, thus compromising renal function directly leading to a reduction in the glomerular filtration rate (GFR) and/or subsequent proteinuria. With this decrease in GFR, patients may need renal replacement therapy (RRT), such as peritoneal dialysis (PD). PD is a high-quality and home-based dialysis therapy for patients with end-stage renal disease (ESRD) and is based on the semi-permeable characteristics of the peritoneum. These patients are exposed to factors which may cause several modifications on the peritoneal membrane. The presence of UT may harm the peritoneum membrane, which in turn can lead to the formation of extracellular vesicles (EVs). EVs are released by almost all cell types and contain lipids, nucleic acids, metabolites, membrane proteins, and cytosolic components from their cell origin. Our research group previously demonstrated that the EVs can be related to endothelial dysfunction and are formed when UTs are in contact with the endothelial monolayer. In this scenario, this review explores the mechanisms of EV formation in CRS, uremia, the peritoneum, and as potential biomarkers in peritoneal dialysis.

NPCdc, a synthetic natriuretic peptide, is a substrate to neprilysin and enhances blood pressure-lowering induced by enalapril in 5/6 nephrectomized rats.

NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 µg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P < 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 µM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes.

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.

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System.

The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called "uremic retention solutes" or "uremic toxins," accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient's therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.