FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells: targeting SDF-1/CXCR4 signaling.

The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

miRNA-203 Modulates Aldosterone Levels and Cell Proliferation by Targeting Wnt5a in Aldosterone-Producing Adenomas.

Context: The aberrant expression or alternation of miRNA in the pathogenesis of aldosterone-producing adenomas (APAs) is still largely unknown. Objective: We investigated the role of miRNA-203 (screened from miRNA microarrays) and elucidated its effects on the Wnt/ß-catenin pathway regarding aldosterone production and cell proliferation in APAs. Methods: miR-203 expression was upregulated or downregulated by transfecting miR-203 mimics or inhibitors into primary APA cells, the human adrenocortical cell line HAC15, and C57BL/6 mice. In vitro and biochemical data were correlated with the respective clinical parameters of APAs to evaluate their clinical importance. Results: The expression of miR-203 in human APA samples was significantly lower than that of peritumor adrenal samples. Tumoral miR-203 abundance correlated negatively with both plasma aldosterone level and tumor size in patients with APAs. miR-203 inhibitors increased aldosterone production and cell proliferation in HAC15 cells, and restoration of expression via miR-203 mimics showed decreased cell proliferation and aldosterone hypersecretion in APA cell cultures. In vivo selective inhibition of miR-203 via intra-adrenal injection of miR-203 inhibitors in mice led to a substantial increase in systolic blood pressure and plasma aldosterone levels. Additionally, the dual-luciferase reporter assay demonstrated that WNT5A is a direct target of miR-203. Furthermore, plasma Wnt5a levels in adrenal vein sampling were helpful in differentiating tumor localization, and preoperative plasma Wnt5a levels predicted the cure of hypertension after adrenalectomy. Conclusion: We have demonstrated that attenuated miR-203 expression in APAs increases aldosterone production and the tumorigenesis of adrenal cells by activating the Wnt5a/ß-catenin pathway.

Long-Term Outcomes in Patients with Incident Chronic Obstructive Pulmonary Disease after Acute Kidney Injury: A Competing-Risk Analysis of a Nationwide Cohort.

Both acute kidney injury (AKI) and chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. However, the incidence of de novo COPD in patients with AKI, and the impact of concurrent COPD on the outcome during post-AKI care is unclear. Patients who recovered from dialysis-requiring AKI (AKI-D) during index hospitalizations between 1998 and 2010 were identified from nationwide administrative registries. A competing risk analysis was conducted to predict the incidence of adverse cardiovascular events and mortality. Among the 14,871 patients who recovered from temporary dialysis, 1535 (10.7%) were identified as having COPD (COPD group) one year after index discharge and matched with 1473 patients without COPD (non-COPD group) using propensity scores. Patients with acute kidney disease superimposed withs COPD were associated with a higher risk of incident ischemic stroke (subdistribution hazard ratio (sHR), 1.52; 95% confidence interval (95% CI), 1.17 to 1.97; p = 0.002) and congestive heart failure (CHF; sHR, 1.61; (95% CI), 1.39 to 1.86; p < 0.001). The risks of incident hemorrhagic stroke, myocardial infarction, end-stage renal disease, and mortality were not statistically different between the COPD and non-COPD groups. This observation adds another dimension to accumulating evidence regarding pulmo-renal consequences after AKI.

Hemojuvelin Predicts Acute Kidney Injury and Poor Outcomes Following Cardiac Surgery.

Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary HJV, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement [NRI] = 0.598; p < 0.001).

Traces of unconscious mental processes in introspective reports and physiological responses.

Unconscious mental processes have recently started gaining attention in a number of scientific disciplines. One of the theoretical frameworks for describing unconscious processes was introduced by Jung as a part of his model of the psyche. This framework uses the concept of archetypes that represent prototypical experiences associated with objects, people, and situations. Although the validity of Jungian model remains an open question, this framework is convenient from the practical point of view. Moreover, archetypes found numerous applications in the areas of psychology and marketing. Therefore, observation of both conscious and unconscious traces related to archetypal experiences seems to be an interesting research endeavor. In a study with 36 subjects, we examined the effects of experiencing conglomerations of unconscious emotions associated with various archetypes on the participants' introspective reports and patterns of physiological activations. Our hypothesis for this experiment was that physiological data may predict archetypes more precisely than introspective reports due to the implicit nature of archetypal experiences. Introspective reports were collected using the Self-Assessment Manikin (SAM) technique. Physiological measures included cardiovascular, electrodermal, respiratory responses and skin temperature of the subjects. The subjects were stimulated to feel four archetypal experiences and four explicit emotions by means of film clips. The data related to the explicit emotions served as a reference in analysis of archetypal experiences. Our findings indicated that while prediction models trained on the collected physiological data could recognize the archetypal experiences with accuracy of 55 percent, similar models built based on the SAM data demonstrated performance of only 33 percent. Statistical tests enabled us to confirm that physiological observations are better suited for observation of implicit psychological constructs like archetypes than introspective reports.

The FYVE domain of Smad Anchor for Receptor Activation (SARA) is required to prevent skin carcinogenesis, but not in mouse development.

Smad Anchor for Receptor Activation (SARA) has been reported as a critical role in TGF-ß signal transduction by recruiting non-activated Smad2/3 to the TGF-ß receptor and ensuring appropriate subcellular localization of the activated receptor-bound complex. However, controversies still exist in previous reports. In this study, we describe the expression of two SARA isoforms, SARA1 and SARA2, in mice and report the generation and characterization of SARA mutant mice with FYVE domain deletion. SARA mutant mice developed normally and showed no gross abnormalities. Further examination showed that the TGF-ß signaling pathway was indeed altered in SARA mutant mice, with the downregulation of Smad2 protein expression. The decreasing expression of Smad2 was caused by enhancing Smurf2-mediated proteasome degradation pathway. However, the internalization of TGF-ß receptors into the early endosome was not affected in SARA mutant mouse embryonic fibroblasts (MEFs). Moreover, the downregulation of Smad2 in SARA mutant MEFs was not sufficient to disrupt the diverse cellular biological functions of TGF-ß signaling, including growth inhibition, apoptosis, senescence, and the epithelial-to-mesenchymal transition. Our results indicate that SARA is not involved in the activation process of TGF-ß signal transduction. Using a two-stage skin chemical carcinogenesis assay, we found that the loss of SARA promoted skin tumor formation and malignant progression. Our data suggest a protective role of SARA in skin carcinogenesis.