Podocyte and glomerular research is center stage for the development of improved preventive and therapeutic strategies for chronic progressive kidney diseases. Held April 3-6, 2016, the 11th ...International Podocyte Conference took place in Haifa and Jerusalem, Israel, where participants from all over the world presented their work on new developments in podocyte research. In this review, we briefly highlight the advances made in characterizing the mechanisms involved in podocyte development, metabolism, acquired injury, and repair, including progress in determining the roles of genetic variants and microRNA in particular, as well as the advances made in diagnostic techniques and therapeutics.
Activation of calcium channels leads to cell injury and proteinuria, while blocking of TRPC5 by novel small molecules (eg, ML204 Merck or AC1903 Cayman Chemical) has been suggested to prevent disease ...progression by preclinical studies, providing new opportunities for future treatment.7 Population disparity in chronic kidney disease has long been a troubling concern. Population-based gene mapping led to the identification of high-frequency variants at the APOL1 genetic locus, which account for much of the disparity in non-diabetic chronic kidney disease of glomerular origin in the African ancestry population.8 This discovery is already impacting day-to-day clinical decision-making regarding kidney donation, and in the assessment of outcomes when transplanting kidneys of high-risk genotype.9 To what extent is this progress decreasing the need for kidney biopsy or transforming the way pathologists examine kidney biopsy samples from pure morphological to molecular analysis? Productive observational global consortia (like PodoNet, the Nephrotic Syndrome Study Network NEPTUNE, the SPOR Canadian Glomerulonephritis Registry and Translational Research Initiative, and others), wherein patient biological samples (kidney biopsy, serum, plasma, and urine) are systematically collected and analysed, are using these investigational platforms.13 Differential transcriptional, proteomic, metabolomic, and epigenomic signatures (such as non-coding RNAs), among others, are being investigated to understand their potential utility in the clinical care of patients with nephrotic syndrome, mainly in terms of identification of novel pathophysiological pathways and molecules, variability of disease progression, prognostic biomarkers, and response to therapy.13 Could this approach lead to mechanism-based interventional clinical trials? A survey of registered clinical trials at ClinicalTrials.gov shows that this is already the case.
Non‐neoplastic stromal cells harvested from patient tumors were identified as tumor‐derived mesenchymal stem cells (MSCs) by their multipotential capacity to differentiate into adipocytes, ...osteoblasts, and chondrocytes and by the expression of MSC specific cell surface markers. These procedures yielded also epithelial cancer cells and their counterpart MSC from gastric carcinoma (GSC1) and lung carcinoma (LC2). While the LC2 cancer cell growth is independent of their LC‐MSC, the GSC1 cancer cell growth is critically dependent on the presence of their counterpart GSC‐MSC or their conditioned medium (CM). The fact that none of the various other tumor‐derived MSCs was able to restore the specific effect of GSC‐MSC on GSC1 cancer cell growth suggests specificity of tumor‐derived MSC, which are specifically recruited and “educated”/reprogrammed by the cancer cells to support tumor growth. Using cytokine array analysis, we were able to demonstrate that GSC1 cell growth is mediated through hepatocyte growth factor (HGF)/c‐MET signaling pathway which is activated exclusively by HGF secreted from GSC‐MSC. An innovative approach demonstrates GSC1‐mediated specific tropism of “naïve” MSC from the adjacent tissue in a tumor specific manner to support tumor progression. The results suggest that specific tumor tropic “naïve” MSC are reprogrammed in a tumor‐specific manner to support gastric tumor progression. Understanding the mechanisms involved in the interactions of the tumor cancer cells and tumor‐derived MSC will constitute the basis for developing multimodal anticancer therapeutic strategies that will also take into account the specific tumor tropism properties of MSC and their reprogramming. Stem Cells 2016;34:1011–1026
Type 1 diabetes generally results from autoimmune destruction of pancreatic islet beta-cells, with consequent absolute insulin deficiency and complete dependence on exogenous insulin treatment. The ...relative paucity of donations for pancreas or islet allograft transplantation has prompted the search for alternative sources for beta-cell replacement therapy. In the current study, we used pluripotent undifferentiated human embryonic stem (hES) cells as a model system for lineage-specific differentiation. Using hES cells in both adherent and suspension culture conditions, we observed spontaneous in vitro differentiation that included the generation of cells with characteristics of insulin-producing beta-cells. Immunohistochemical staining for insulin was observed in a surprisingly high percentage of cells. Secretion of insulin into the medium was observed in a differentiation-dependent manner and was associated with the appearance of other beta-cell markers. These findings validate the hES cell model system as a potential basis for enrichment of human beta-cells or their precursors, as a possible future source for cell replacement therapy in diabetes.
Although it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here, we describe a method to measure the ...origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (
) gene and to the identical, paralogous hemoglobin subunit delta (
) region in sperm cells from both African and European donors. The
region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa, and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the
region studied. Finally, the rate of the 20A→T mutation, called the "HbS mutation" when it appears in
, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African
ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.
It has been the policy of Rambam Maimonides Medical Journal to limit the number of editorials published. However, silence and standing on the sidelines is not an option in light of the atrocities and ...inhumanity we witnessed on October 7. The savagery of the Hamas massacre was executed indiscriminately upon children, women, older people (some of whom are Holocaust survivors), infants, and even medical professionals caring for the casualties. Currently, there are about 230 women, men, children, and babies being held hostage by Hamas; among them are cancer patients and others with serious disorders, doctors, and other medical professionals. We cannot rest and must address the plight of our hostages who are being held by terrorists motivated by hatred and showing no respect for life, whether that of their enemies, their own people, or even themselves. ...
Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case–control study design. Analysis of genotypes at the APOL1 kidney ...disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension.
Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus ...(JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype.
Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants.
In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P = 0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney.
Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.
Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk ...modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans.
We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed.
Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis meta-analysis P = 0.0070; odds ratio (OR) = 1.29; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein.
Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.
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