We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.
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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.
Anhydroecgonine methyl ester (AEME), also called methylecgonidine, is a pyrolysis product of crack cocaine that is neurotoxic and potentiates cocaine-induced sensitization. The sensitization induced by drugs of abuse can be influenced by melatonin, a neuroprotective pineal hormone. In the same way, drugs of abuse like alcohol and methamphetamine can modify melatonin synthesis. The aim of the present work was to investigate the AEME effects on melatonin synthesis in the rat pineal gland. Neurotransmitter systems involved in its effects, antioxidant enzyme activities and the melatonin protective role in AEME-induced toxicity were also evaluated. The animals were injected with AEME i.p. (1.12 mg per kg of body weight per day) or vehicle for 10 consecutive days and the nocturnal pineal melatonin synthesis profile and SOD, GPx and GR activities in the cerebral cortex and hippocampus were assessed. Cultured pineal glands were incubated with AEME for 30 min or 48 h before norepinephrine stimulation and melatonin synthesis, arylalkylamine -acetyltransferase activity, cAMP and [Ca]i were determined. The involvement of cholinergic and glutamatergic systems was analyzed using different antagonists. The protective role of melatonin in AEME toxicity on hippocampal neurons was evaluated by a viability assay. AEME impaired melatonin synthesis both and and this effect seems to be mediated by muscarinic receptors and [Ca]i elevation. AEME reduced neuronal viability and melatonin was able to protected hippocampal neurons against AEME toxicity. The melatonin synthesis impairment observed could lead to the worsening of the direct AEME neurotoxicity and to the exacerbation of the crack cocaine addiction and sensitization.
ObjectivesThe cardio‐renal syndrome comprises a set of pathophysiological kidney‐heart interactions. Renal injury promotes release of inflammatory cytokines (CTK), which may act through cardiac TLR and lead to CH, as well as AngII. This study aims to investigate a possible interaction between TLR and RAS in CH model induced by IRI.MethodsC57BL/6 male mice (n=84) treated with Losartan (Los‐10 mg/kg) or Enalapril (Ena‐40 mg/kg) were subjected to surgical occlusion of left renal pedicle and kept under observation for 20d. IRI, CH and systolic blood pressure (SBP) were assessed by morphologic, molecular and functional parameters, as well as tail‐cuff plethysmography and electrocardiography (ECG) before and after surgery. Serum/cardiac RAS components, TLR2/TLR4 and inflammatory CTK were evaluated by Real‐Time PCR, protein expression and ELISA.ResultsThe successfully‐performed IRI induced an enhancement of serum IL‐6, TNF‐a and IFN‐y (p<0.001) and did not promote SBP alteration. CH was observed after 12d of reperfusion, when cardiac AT1, ACE2, TLR2/TLR4 levels were increased (p<0.001). Los/Ena prevented CH (p<0.001) without changing SBP and modulated serum AngII and CTK levels (p<0.05). Also, ECG showed an improvement in cardiac function.ConclusionThe presented data shows that RAS inhibition is able to completely prevent CH via regulation of cardiac TLR and serum AngII/CTK levels, suggesting the existence of a key cross‐talk between TLR and RAS in CH induced by IRI. Financial Support: FAPESP; CNPq.
BackgroundIt is known that renal ischemia reperfusion (I/R) generates a systemic inflammatory state, promoting molecular and morphological changes in the heart tissue, but the mechanisms remain unknown. TLRs are largely studied in the heart and are known to participate of inflammatory process, moreover it has been demonstrated their role in cardiac hypertrophy (CH) development.AimThe aim of this study was to investigate whether cardiac TLRs pathways are involved in renal I/R‐induced CH.Methods/ResultsC57BL/6J, TLR2‐/‐ and TLR4‐/‐ mice were subjected to unilateral 60 min renal ischemia followed by reperfusion for 5, 8, 12 and 15 days. A serum peak of inflammatory cytokines was observed after 5 days of reperfusion. Heart weight/tibia length (HW/TL) ratio was increased after 12 days of reperfusion, as well as CH markers BNP and alpha‐actin. Cardiac electrical activity showed longer QT, QTc and action potential duration after 15 days. Cardiac TLRs, NF‐kB, MyD88, HSP60 and 70 mRNA levels were increased in the 15‐days group. After 15 days of reperfusion, the absence of TLRs prevented CH development, as reflected by similar values of HW/TL compared to transgenic non‐ischemic mice, as well as lower expression of HSP and NF‐kB, suggesting that renal IR‐induced increase of these molecules was prevented.ConclusionsThese results indicate that (i) TLRs play a key role on renal IR‐induced CH; (ii) prevention of hypertrophic response was independent of renal function recovery; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile.
Objectives: The cardio‐renal syndrome comprises a set of pathophysiological kidney‐heart interactions. Renal inflammatory conditions are able to promote the release of inflammatory cytokines, which may act through cardiac TLR, promoting cardiovascular diseases such as cardiac hypertrophy (CH), as well as angiotensin II. This study aims to investigate a possible interaction between TLR and RAS in a model of CH induced by ischemic renal injury. Methods: C57BL/6 male mice (n=85) were subjected to surgical occlusion of left renal pedicle. Mice were treated with Los (10 mg/kg/day) or Ena (40 mg/kg/day) and kept under observation for 12, 15 or 20 days of reperfusion (REP). Kidney injury and CH were assessed by morphologic and molecular parameters. Cardiac and serum cytokines and protein and mRNA levels of cardiac RAS components and TLR2 and TLR4 were evaluated. Results: The succesfully‐performed ischemic protocol induced CH after 12d of REP, which was accompanied by enhanced IL‐6 levels in serum. CH were completely reversed by Los and Ena treatment. At the same time point, cardiac AT1, ACE2, TLR2 and TLR4 levels were increased (p<0.001). Treatment with RAS inhibitors abolished this increase to levels similar to control group. Conclusion: RAS may modulate CH through regulation of TLRs levels in the heart, suggesting the existence of a important cross‐talk between TLR and RAS in CH induced by renal ischemia/reperfusion.
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