Heart failure (HF) manifestation and progression are driven by systemic activation of neuroendocrine signaling cascades, such as the renin-angiotensin aldosterone system (RAAS). Fibroblast growth factor 23 (FGF23), an endocrine hormone, is linked to HF and cardiovascular mortality. It is also a mediator of left-ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is proposed to trigger pathological signaling mediated by Ca-regulated transcriptional pathways. In the present study, we investigated Ca-dependent signaling of FGF23 in ventricular cardiomyocytes and its association with angiotensin II (ATII). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23 induced hypertrophy as observed by an increase in cell area and hypertrophic gene expression. Furthermore, FGF23 activates nuclear Ca-regulated CaMKII-HDAC4 pathway, similar to ATII. In addition to a global increase in cytoplasmic Ca, FGF23, like ATII, induced inositol 1, 4, 5-triphosphate (IP3)-induced Ca release from the nucleoplasmic Ca store, associated with cellular hypertrophy. Interestingly, ATII receptor antagonist, losartan, significantly attenuated FGF23-induced changes in Ca homeostasis and cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. In addition, application of FGF23 increased intracellular expression of ATII peptide and its secretion in NRVMs, confirming the participation of ATII. In conclusion, FGF23 and ATII share a common mechanism of IP3-nuclear Ca-dependent cardiomyocyte hypertrophy. FGF23-mediated cellular hypertrophy is associated with increased production and secretion of ATII by cardiomyocytes. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular cardiomyocytes.

Dehydration has a profound influence on neuroexcitability. The mechanisms remained, however, incompletely understood. The present study addressed the effect of water deprivation on gene expression in the brain. To this end, animals were exposed to a 24 hours deprivation of drinking water and neuronal gene expression was determined by microarray technology with subsequent confirmation by RT-PCR. As a result, water deprivation was followed by significant upregulation of clathrin (light polypeptide Lcb), serum/glucocorticoid-regulated kinase (SGK) 1, and protein kinase A (PRKA) anchor protein 8-like. Water deprivation led to downregulation of janus kinase and microtubule interacting protein 1, neuronal PAS domain protein 4, thrombomodulin, purinergic receptor P2Y - G-protein coupled 13 gene, gap junction protein beta 1, neurotrophin 3, hyaluronan and proteoglycan link protein 1, G protein-coupled receptor 19, CD93 antigen, forkhead box P1, suppressor of cytokine signaling 3, apelin, immunity-related GTPase family M, serine (or cysteine) peptidase inhibitor clade B member 1a, serine (or cysteine) peptidase inhibitor clade H member 1, glutathion peroxidase 8 (putative), discs large (Drosophila) homolog-associated protein 1, zinc finger and BTB domain containing 3, and H2A histone family member V. Western blotting revealed the downregulation of forkhead box P1, serine (or cysteine) peptidase inhibitor clade H member 1, and gap junction protein beta 1 protein abundance paralleling the respective alterations of transcript levels. In conclusion, water deprivation influences the transcription of a wide variety of genes in the brain, which may participate in the orchestration of brain responses to water deprivation.

Retinitis Pigmentosa involves a hereditary degeneration of photoreceptors by as yet unresolved mechanisms. The secretable protein α-Klotho has a function related to ageing processes, and α-Klotho-deficient mice have reduced lifespan and declining functions in several tissues. Here, we studied Klotho in connection with inherited photoreceptor degeneration. Increased nuclear immunostaining for α-Klotho protein was seen in degenerating photoreceptors in four different Retinitis Pigmentosa models (rd1, rd2 mice; P23H, S334ter rhodopsin mutant rats). Correspondingly, in rd1 retina α-Klotho mRNA expression was significantly up-regulated. Moreover, immunostaining for another Klotho family protein, β-Klotho, also co-localized with degenerating rd1 photoreceptors. The rd1 retina displayed reduced levels of fibroblast growth factor 15, a member of the fibroblast growth factor subfamily for which Klotho acts as a co-receptor. Exogenous α-Klotho protein added to retinal explant cultures did not affect cell death in rd1 retinae, but caused a severe layer disordering in wild-type retinae. Our study suggests Klotho as a novel player in the retina, with a clear connection to photoreceptor cell death as well as with an influence on retinal organization.

: We aimed to explore left atrial (LA) remodeling in the patients with solid cancer before initiation of chemo- or radiotherapy. This retrospective investigation included 92 chemo- and radiotherapy-naive cancer patients and 40 age- and gender-matched controls with a similar cardiovascular risk profile as the cancer group. All participants underwent comprehensive echocardiographic examination before the start of chemo- or radiotherapy. LA phasic function was evaluated in volumetric and strain method. Indexed minimal and pre-A LA volumes were significantly higher in the cancer patients. Total and passive LA emptying fraction (EF) were significantly lower, whereas active LAEF was significantly higher in the cancer patients. LA total longitudinal strain was significantly lower in the cancer patients. Strain rate analysis of LA phasic function showed that LA function during systole and early diastole was reduced in the cancer group, while it was increased during late diastole. These findings indicated that LA reservoir and conduit functions, assessed with LA volumetric and strain analysis, were deteriorated in the cancer group. On the other hand, LA booster pump function was elevated in the cancer group in comparison with the controls. In the whole population, cancer was associated with reduced LA total longitudinal strain independently of age, gender, BMI, LV hypertrophy, E/e’ ratio, diabetes, and hypertension. LA phasic function was impaired in the chemo- and radiotherapy-naive cancer patients in comparison with the control group. Cancer, LV hypertrophy, and hypertension were associated with reduced LA longitudinal strain independently of other important clinical parameters.

Glycogen synthase kinase 3 (GSK3) plays a decisive role in the regulation of multiple functions. GSK3 is phosphorylated and its activity inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which are in turn activated by growth factors through phosphoinositide (PI) 3 kinase signaling. PI3/PKB/Akt/SGK-dependent inhibition of GSK3 is disrupted in gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3α,ß (gsk3 ( KI )) where the serine of the PKB/SGK phosphorylation site has been replaced by alanine. Recent experiments revealed that blood pressure is significantly higher in those mice than in wild type mice (gsk3 ( WT )). The present study was performed to elucidate the underlying cause. Blood pressure was determined with the tail cuff method, heart rate by ECG measurements, catecholamine concentrations by ELISA, and vanillylmandelic acid by high pressure liquid chromatography. As a result, blood pressure and heart rate were significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. The α-adrenergic blocker prazosin (1 μg/g body weight, b.w.) and the ganglion blocker hexamethonium (40 μg/g b.w.) decreased blood pressure to a larger extent in gsk3 ( KI ) than in gsk3 ( WT ) mice and virtually abrogated the difference between genotypes. Similarly, the β-adrenergic blocker atenolol (5 μg/g b.w.) decreased the heart rate to a larger extent in gsk3 ( KI ) than in gsk3 ( WT ) mice and again dissipated the difference of heart rate between genotypes. Plasma epinephrine and norepinephrine concentrations, as well as urinary excretion of vanillylmandelic acid, were significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. The observations reveal a completely novel function of PKB/Akt/SGK-dependent GSK3 signaling, i.e., regulation of catecholamine release.