Protective Actions of PPAR-γ Activation in Renal Endothelium

Renal endothelial damage is pivotal in the initiation and progression of renal disease. Damaged renal endothelium may be regenerated through proliferation of local endothelium and circulation-derived endothelial progenitor cells. Activation of the PPAR-γ-receptors present on endothelial cells affects their cellular behavior. Proliferation, apoptosis, migration, and angiogenesis by endothelial cells are modulated, but may involve both stimulation and inhibition depending on the specific circumstances. PPAR-γ-receptor activation stimulates the production of nitric oxide, C-type natriuretic peptide, and superoxide dismutase, while endothelin-1 production is inhibited. Together, they augment endothelial function, resulting in blood pressure lowering and direct renoprotective effects. The presentation of adhesion molecules and release of cytokines recruiting inflammatory cells are inhibited by PPAR-γ-agonism. Finally, PPAR-γ-receptors are also found on endothelial progenitor cells and PPAR-γ-agonists stimulate progenitor-mediated endothelial repair. Together, the stimulatory effects of PPAR-γ-agonism on endothelium make an important contribution to the beneficial actions of PPAR-γ-agonists on renal disease

ACE Inhibition in Anti-Thy1 Glomerulonephritis Limits Proteinuria but Does Not Improve Renal Function and Structural Remodeling

www.karger.com/nne This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online version of the article only. Distribution for non-commercial purposes only.

Controlling cellular plasticity to improve in vitro models for kidney regeneration

Given the increasing prevalence of end-stage kidney disease, the high morbidity and mortality of dialysis treatment, and the shortage of donor kidneys, the field of nephrology is progressively shifting its focus to regenerative medicine. In particular, both the development of a bioartificial kidney and the improvement of kidney-mimicking systems developed in vitro (e.g. organoids or tubuloids) for implantation purposes are attractive therapeutic strategies. However, a major hurdle to overcome with the current kidney cell models available is the limited control over cellular plasticity to augment cell-type-specific functionality. In this review, we summarize the main knowledge on important factors known to drive or affect maturation of kidney epithelial cells. This might aid in the advancement of in vitro kidney models to enable their use in regenerative medicine

Smooth Muscle Progenitor Cells: Friend or Foe in Vascular Disease?

The origin of vascular smooth muscle cells that accumulate in the neointima in vascular diseases such as transplant arteriosclerosis, atherosclerosis and restenosis remains subject to much debate. Smooth muscle cells are a highly heterogeneous cell population with different characteristics and markers, and distinct phenotypes in physiological and pathological conditions. Several studies have reported a role for bone marrow-derived progenitor cells in vascular maintenance and repair. Moreover, bone marrow-derived smooth muscle progenitor cells have been detected in human atherosclerotic tissue as well as in in vivo mouse models of vascular disease. However, it is not clear whether smooth muscle progenitor cells can be regarded as a ‘friend’ or ‘foe’ in neointima formation. In this review we will discuss the heterogeneity of smooth muscle cells, the role of smooth muscle progenitor cells in vascular disease, potential mechanisms that could regulate smooth muscle progenitor cell contribution and the implications this may have on designing novel therapeutic tools to prevent development and progression of vascular disease

Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions

Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs’ viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.</p

Advances and potential of regenerative medicine in pediatric nephrology

The endogenous capacity of the kidney to repair is limited, and generation of new nephrons after injury for adequate function recovery remains a need. Discovery of factors that promote the endogenous regenerative capacity of the injured kidney or generation of transplantable kidney tissue represent promising therapeutic strategies. While several encouraging results are obtained after administration of stem or progenitor cells, stem cell secretome, or extracellular vesicles in experimental kidney injury models, very little data exist in the clinical setting to make conclusions about their efficacy. In this review, we provide an overview of the cutting-edge knowledge on kidney regeneration, including pre-clinical methodologies used to elucidate regenerative pathways and describe the perspectives of regenerative medicine for kidney patients

Progression of coronary artery calcification in conventional hemodialysis, nocturnal hemodialysis, and kidney transplantation

Introduction Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients. Methods We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (>= 4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (Delta CAC SQRV) using linear mixed models. Reference category was conventional hemodialysis. Results The mean age of the study population was 53 +/- 13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models. Conclusions Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk

Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study

Background: Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we investigated the gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes compared to endothelial progenitor cells from healthy subjects. Furthermore, we studied the effect of folic acid on gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes. Methods: We used microarray analysis to investigate the gene expression profiles of endothelial progenitor cells from type 1 diabetes patients before (n = 11) and after a four week period of folic acid supplementation (n = 10) compared to the gene expression profiles of endothelial progenitor cells from healthy subjects (n = 11). The probability of genes being differentially expressed among the classes was computed using a random-variance t-test. A multivariate permutation test was used to identify genes that were differentially expressed among the two classes. Functional classification of differentially expressed genes was performed using the biological process ontology in the Gene Ontology database. Results: Type 1 diabetes significantly modulated the expression of 1591 genes compared to healthy controls. These genes were found to be involved in processes regulating development, cell communication, cell adhesion and localization. After folic acid treatment, endothelial progenitor cell gene expression profiles from diabetic patients were similar to those from healthy controls. Genes that were normalized by folic acid played a prominent role in development, such as the transcription factors ID1 and MAFF. Few oxidative-stress related genes were affected by folic acid. Conclusion: Folic acid normalizes endothelial progenitor cell gene expression profiles of patients with type 1 diabetes. Signaling pathways modulated by folic acid may be potential therapeutic targets to improve endothelial progenitor cell function

Kidney Organoids and Tubuloids

In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine

Коррекция состояния иммунной системы крыс с адъювантным артритом введением липидной фракции плаценты

Введення ліпідної фракції плаценти, отриманої методом кріогенного молекулярного фракціонування, на фоні розвитку ад’ювантного артриту оказує корегуючий вплив у відношенні як вмісту, так і функціональної активності регуляторних Т-клітин регіональних лімфовузлів, що призводить до зниження інтенсивності клінічних ознак захворювання.Injection of placental lipid fraction obtained by cryogenic molecular fractionation method on the background of adjuvant arthritis development has a correcting influence in relation to both content and functional activity of regulatory T-cells of regional lymph nodes which leads to a decrease in intensity of clinical signs of the disease