Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model

Background/Aims: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. Methods: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinβ1 in addition to Angiotensin-II and TGF-β1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-β1 or receptor blockers. Results: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinβ1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-β1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. Conclusions: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-β1, culminating in apoptosis and detachment of non-viable podocytes

“Losing Faith in My Body”: Body Image in Individuals Diagnosed with End-Stage Renal Disease as Reflected in Drawings and Narratives

Chronic kidney disease (CKD) and the dependency on dialysis is an abrupt life-changing event that harms a patient’s life (e.g., social relationships, work, and well-being). This study aimed to examine how individuals who undergo chronic dialysis due to failure end-stage renal disease perceive their bodies, as reflected in drawings and narratives. Following ethical approval and signing a consent form to participate in the study, 29 adults between the ages of 20 and 85 who have undergone dialysis filled out an anonymous questionnaire that consisted of the following measures: The Center for Epidemiological Studies—Depression (CES-D), The Multidimensional Body-Self Relations Questionnaire (MBSRQ), and The MOS 36-Item Short-Form Health Survey (SF-36). After completion, they were asked to draw their self-figure before and after being diagnosed and narrate it. The data were quantitatively and narratively analyzed. The results revealed high levels of depression and concerns regarding body fitness and weight. Few significant differences were noted between self-figured drawings before and after the diagnosis, such as the body line and gender markers. Additionally, Fitness Evaluation and Overweight Preoccupation were significant among the participants

Effect of Peripheral Electrical Stimulation (PES) on Nocturnal Blood Glucose in Type 2 Diabetes: A Randomized Crossover Pilot Study

<div><p>Background</p><p>Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM).</p><p>Methods</p><p>Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation.</p><p>Results</p><p>We found that during the active period, the most significant effect was on nocturnal glucose control (<i>P</i> < 0.0004), as well as on pre-meal mean glucose levels (<i>P</i> < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (<i>P</i> = 0.07). A reduction in serum cortisol (<i>P</i> < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded.</p><p>Conclusions</p><p>These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02727790" target="_blank">NCT02727790</a></p></div

Cortisol levels at the end of the PES and control periods.

<p>a. The cortisol outcome of the two-period crossover trial presented for the CT (n = 6) and TC (n = 5) arms. CT: Control-Treatment arm, TC: Treatment-Control arm. b. Mean Cortisol levels (n = 11), Data are means ± SEM.</p

CONSORT flow chart and study design.

<p>a. A Crossover design with a two-week washout period separating each trial. b. Summary of study visits and procedures. PES–Home care peripheral electrical stimulation treatment, MGTT–meal glucose tolerance test. In visits V1-V6 and the follow up (FU) visit, all patients underwent a clinical evaluation, and BT (blood tests) were taken. c. PES signal treatment pattern.</p

Baseline patients' characteristics.

<p>Baseline patients' characteristics.</p

Multi-parametric, heat map analysis.

<p>Each column represents a single subject, and the color scale indicates the normalized value of each one of the parameters. The parameters are ordered by hierarchical clustering using the Euclidean distance metric algorithm. Cluster (A) parameters are related to mechanisms that involve HGP pathways, where cluster (B) parameters are more influenced from glucose utilization. More details are found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168805#pone.0168805.s004" target="_blank">S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168805#pone.0168805.s005" target="_blank">S3</a> Tables.</p

Fasting and Postprandial States Results (CGM data).

<p>Fasting and Postprandial States Results (CGM data).</p