Lerman, Lilach O.

Endothelial progenitor cells (EPCs) patrols the circulation and contributes to endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave therapy (SW) can induce angiogenesis and restore the STK microcirculation, but the underlying mechanism remains unclear. We tested the hypothesis that SW increases EPC homing to the swine STK, associated with capillary regeneration. Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six sessions of low-energy SW (biweekly for three consecutive weeks) or left untreated. Four weeks after completion of treatment, we assessed EPC (CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor (SDF)-1 in the inferior vena cava and the STK vein and artery, as well as urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β. Subsequently, we assessed STK morphology, capillary count, and expression of the proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide synthase ex vivo. A 3-wk low-energy SW regimen improved STK structure, capillary count, and function in ARAS+SW, and EPC numbers and gradients across the STK decreased. Plasma SDF-1 and renal expression of angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and integrin-1β tended to rise during the SW regimen. In conclusion, SW improves ischemic kidney capillary density, which is associated with, and may be at least in part mediated by, promoting EPCs mobilization and homing to the stenotic kidney.

Cellular senescence, a permanent arrest of cell proliferation, is characterized by a senescence-associated secretory phenotype (SASP), which reinforces senescence and exerts noxious effects on adjacent cells. Recent studies have suggested that transplanting small numbers of senescent cells suffices to provoke tissue inflammation. We hypothesized that senescent cells can directly augment renal injury. Primary scattered tubular-like cells (STCs) acquired from pig kidneys were irradiated by 10 Gy of cesium radiation, and 3 wk later cells were characterized for levels of senescence and SASP markers. Control or senescent STCs were then prelabeled and injected (5 × 105 cells) into the aorta of C57BL/6J mice. Four weeks later, renal oxygenation was studied in vivo using 16.4-T magnetic resonance imaging and function by plasma creatinine level. Renal markers of SASP, fibrosis, and microvascular density were evaluated ex vivo. Per flow cytometry, irradiation induced senescence in 80–99% of STCs, which showed increased gene expression of senescence and SASP markers, senescence-associated β-galactosidase staining, and cytokine levels (especially IL-6) secreted in conditioned medium. Four weeks after injection, cells were detected engrafted in the mouse kidneys with no evidence for rejection. Plasma creatinine and renal tissue hypoxia increased in senescent compared with control cells. Senescent kidneys were more fibrotic, with fewer CD31+ endothelial cells, and showed upregulation of IL-6 gene expression. Therefore, exogenously delivered senescent renal STCs directly injure healthy mouse kidneys. Additional studies are needed to determine the role of endogenous cellular senescence in the pathogenesis of kidney injury and evaluate the utility of senolytic therapy.

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells–derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8 + T cells were detected in stenotic kidneys treated with Lean-EVs compared with MetS-EVs, and renal vein levels of interleukin-1β were reduced. In vitro, coculture of Lean-EVs with activated T cells led to greater TGF-β-dependent regulatory T cells induction than did MetS-EVs. Therefore, the beneficial effects of mesenchymal stem cells–derived EVs on injured kidneys might be partly mediated by their content of TGF-β signaling components, which permitting increased Treg preponderance. Modulating EV cargo and transforming their functionality might be useful for renal repair.

Importance. Obesity is a worsening epidemic worldwide. Effective and accessible weight loss programs to combat obesity on a large scale are warranted, but a need for frequent face-to-face care might impose a limitation. Objective. To evaluate whether individuals following a weight loss program based on a mobile application, wireless scale, and nutritional program but no face-to-face care can achieve clinically significant weight loss in a large cohort. Design. Retrospective observational analysis. Setting. China from October 2016 to December 2017. Participants. Mobile application users with a minimum of 2 weights (baseline and ≥35 days). Intervention. A commercial (Weijian Technologies) weight loss program consisting of a dietary replacement, self-monitoring using a wireless home scale, and frequent guidance via mobile application. Main Outcome. Mean weight change around 42, 60, 90, and 120 days after program initiation with subgroup analysis by gender, age, and frequency of use. Results. 251,718 individuals, with a mean age of 37.3 years (SD: 9.86) (79% female), were included with a mean weight loss of 4.3 kg (CI: ±0.02) and a mean follow-up of 120 days (SD: 76.8 days). Mean weight loss at 42, 60, 90, and 120 d was 4.1 kg (CI: ±0.02), 4.9 kg (CI: ±0.02), 5.6 kg (CI: ±0.03), and 5.4 kg (CI: ±0.04), respectively. At 120 d, 62.7% of participants had lost at least 5% of their initial weight. Both genders and all usage frequency tertiles showed statistically significant weight loss from baseline at each interval (P<0.001), and this loss was greater in men than in women (120 d: 6.5 vs. 5.2 kg; P<0.001). The frequency of recording (categorized as high-, medium-, or low-frequency users) was associated with greater weight loss when comparing high, medium, and low tertile use groups at all time intervals investigated (e.g., 120 d: −8.6, −5.6, and −2.2 kg, respectively; P<0.001). Conclusions. People following a commercially available hybrid weight loss program using a mobile application, wireless scale, and nutritional program without face-to-face interaction on average achieved clinically significant short- and midterm weight loss. These results support the implementation of comparable technologies for weight control in a large population.

Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin–eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD.

Abstract BACKGROUND Mitochondria modulate endothelial cell (EC) function, but may be damaged during renal disease. We hypothesized that the ischemic and metabolic constituents of swine renovascular disease (RVD) induce mitochondrial damage and impair the function of renal artery ECs. METHODS Pigs were studied after 16 weeks of metabolic syndrome (MetS), renal artery stenosis (RAS), or MetS + RAS, and Lean pigs served as control (n = 6 each). Mitochondrial morphology, homeostasis, and function were measured in isolated primary stenotic-kidney artery ECs. EC functions were assessed in vitro, whereas vasoreactivity of renal artery segments was characterized in organ baths. RESULTS Lean + RAS and MetS + RAS ECs showed increased mitochondrial area and decreased matrix density. Mitochondrial biogenesis was impaired in MetS and MetS + RAS compared with their respective controls. Mitochondrial membrane potential similarly decreased in MetS, Lean + RAS, and MetS + RAS groups, whereas production of reactive oxygen species increased in MetS vs. Lean, but further increased in both RAS groups. EC tube formation was impaired in MetS, RAS, and MetS + RAS vs. Lean, but EC proliferation and endothelial-dependent relaxation of renal artery segments were blunted in MetS vs. Lean, but further attenuated in Lean + RAS and MetS + RAS. CONCLUSIONS MetS and RAS damage mitochondria in pig renal artery ECs, which may impair EC function. Coexisting MetS and RAS did not aggravate EC mitochondrial damage in the short time of our in vivo studies, suggesting that mitochondrial injury is associated with impaired renal artery EC function.

Introduction Severe obesity is a growing epidemic that causes significant morbidity and mortality, and is particularly difficult to reverse. Efficacious and cost-effective interventions are needed to combat this epidemic. This study hypothesized that obese people (body mass index (BMI) ≥35 kg/m 2 ) using a remote weight-loss program combining a mobile application, wireless scales, and low-calorie meal replacement would experience clinically significant weight loss. Methods This study was a retrospective observational analysis of 8275 individuals with a baseline BMI ≥35 kg/m 2 who used a remote weight-loss program combining mobile applications, frequent self-weighing, and calorie restriction via meal replacement for a minimum of 35 days. Weight changes were evaluated at multiple intervals (42, 60, 90, and 120 days), and weight loss was evaluated for all and for pre-specified subgroups based on demographic features and frequency of self-weighing. Results Mean weight loss at 42 days ( N = 6781) was 8.1 kg (margin of error (MOE) = 0.126 kg) with 73.6% of users experiencing >5% total body weight loss. Both men (9.1 kg; MOE = 0.172 kg; 7.9% from baseline) and women (7.1 kg; MOE = 0.179 kg; 7.2% from baseline) experienced significant weight loss. At the 120-day interval ( N = 2914), mean weight loss was 14 kg (MOE = 0.340 kg), 13% total body weight loss from baseline, and 82.3% of participants had lost >5% of their initial body weight. The decrease in body-fat percent correlated well with weight loss ( R = 0.92; p < 0.001). Conclusions In a large cohort of individuals with class II or III obesity, a remote weight-loss program combining mobile applications, daily self-weighing, and calorie restriction via meal replacement resulted in dramatic weight loss among subjects who were active users when evaluated through a retrospective observational analysis.

Introduction: Metabolic Syndrome represents a constellation of findings known to increase cardiovascular risk and all-cause mortality and is becoming more frequent in China. Smartphone applications may provide a cost-effective method to engage in weight loss and improve metabolic syndrome components. Methods: Prospective study of changes in weight and metabolic syndrome risk factors at 6 weeks and 6 months using a smartphone application utilizing a wireless scale, meal replacement biscuits and e-coaching in China. All participants had or were at high risk for metabolic syndrome and all interaction was online, without face to face contact. Results: 218 individuals ,55% female, participated. Median weight loss at 6 weeks and 6 months was 7.3kg and 8.4 kg (P<0.001) respectively. At baseline, 60% met a diagnosis of metabolic syndrome this dropped to 38% at 6 weeks (P<0.001) and stayed at 38% at 6 months (P<0.001). At 6 week the prevalence of all components of metabolic syndrome were improved (P<0.05) except HDL. Conclusions: A smartphone weight loss platform that utilizes a wireless scale, meal replacement biscuits and e-coaching was associated with significant weight loss and improvement in several metabolic syndrome components at 6 weeks and 6 months. This program may provide a scalable intervention against metabolic syndrome, especially in developing countries such as China.

AbstractCD34+ cells are haematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the haematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischaemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischaemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction (AMI), heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review, we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, AMI, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.