scholarly journals A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients

2021 ◽  
Author(s):  
Elena Garreta ◽  
Praticia Prado ◽  
Megan L. Stanifer ◽  
Vanessa Monteil ◽  
Carmen Hurtado del Pozo ◽  
...  
Keyword(s):  
Human Kidney ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Loads ◽  
Glucose Exposure ◽  
Genetic Deletion ◽  
Membrane Components ◽  
Kidney Organoids

SARS-CoV-2 infections lead to a high risk of hospitalization and mortality in diabetic patients. Why diabetic individuals are more prone to develop severe COVID-19 remains unclear. Here, we established a novel human kidney organoid model that mimics early hallmarks of diabetic nephropathy. High oscillatory glucose exposure resulted in metabolic changes, expansion of extracellular membrane components, gene expression changes determined by scRNAseq, and marked upregulation of angiotensin-converting enzyme 2 (ACE2). Upon SARS-CoV-2 infection, hyperglycemic conditions lead to markedly higher viral loads in kidney organoids compared to normoglycemia. Genetic deletion of ACE2, but not of the candidate receptor BSG/CD147, in kidney organoids demonstrated the essential role of ACE2 in SARS-CoV-2 infections and completely prevented SARS-CoV-2 infection in the diabetogenic microenvironment. These data introduce a novel organoid model for diabetic kidney disease and show that diabetic-induced ACE2 licenses the diabetic kidney to enhanced SARS-CoV-2 replication.

scholarly journals Association between PTX3 and PVT1 genetic polymorphisms and the risk of diabetic kidney disease in type 2 diabetic patients

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Sindhu Varghese ◽  
Gowtham Kumar Subburaj
Keyword(s):  
Kidney Disease ◽  
Genetic Polymorphisms ◽  
Diabetic Kidney Disease ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Type 2 Diabetic

Abstract Background Very few studies have investigated the role of PTX3 and PVT1 genetic polymorphisms and their association in the progression of diabetic kidney diseases. Diabetic kidney disease (DKD) is a prominent reason of end-stage renal disease and also known to be involved in the high mortality rate of cardiovascular diseases. The current study has examined the role of PTX3 and PVT1 genetic polymorphisms in the development of diabetic kidney disease in type 2 diabetic patients. Results A significant difference between the genotypes and alleles of the rs2305619 polymorphism was observed in the diabetic patients with DKD when compared with the control group. The frequency of GG genotype was observed to be high in diabetic patients with DKD when compared to the other two groups. This specified that diabetic patients with GG genotype are at an increased risk to develop DKD. However, PVT1 (G/A) polymorphism did not show any association in the allele and genotypic frequencies with DKD when compared with T2DM and controls. Conclusion Our results propose a major influence of GG genotype of rs2305619 polymorphism to be significantly linked with an increased risk of DKD in type 2 diabetic patients.

scholarly journals Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy

2020 ◽  
Author(s):  
Jin Won Kim ◽  
Sun Ah Nam ◽  
Eunjeong Seo ◽  
Jong Young Lee ◽  
Dohui Kim ◽  
...  
Keyword(s):  
Human Kidney ◽  
Kidney Organoids

scholarly journals Revisiting The Role of Notch in Nephron Segmentation: Notch is required for proximal, not distal fate selection during mouse and human nephrogenesis

2021 ◽  
Author(s):  
Kathryn Duvall ◽  
Lauren Bice ◽  
Alison J Perl ◽  
Naomi Pode Shakked ◽  
Praneet Chaturvedi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Human Kidney ◽  
Distal Tubule ◽  
Rna Seq ◽  
Early Markers ◽  
Nephron Segmentation ◽  
Human Ipsc ◽  
Kidney Organoids ◽  
In Cells

Notch signaling promotes maturation of nephron epithelia, but its proposed contribution to nephron segmentation into proximal and distal domains has been called into doubt. We leveraged single cell and bulk RNA-seq, quantitative immunofluorescent lineage/fate tracing, and genetically modified human iPSC to revisit this question in developing mouse kidneys and human kidney organoids. We confirmed that Notch signaling is needed for maturation of all nephron lineages, and thus mature lineage markers fail to detect a fate bias. By contrast, early markers identified a distal fate bias in cells lacking Notch2, and a concomitant increase in early proximal and podocyte fates in cells expressing hyperactive Notch1 was observed. Orthogonal support for a conserved role for Notch signaling in the distal/proximal axis segmentation is provided by the ability of Nicastrin-deficient hiPSCs-derived organoids to differentiate into TFA2B+ distal tubule and CDH1 connecting segment progenitors, but not into HNF4A+ or LTL+ proximal progenitors.

Autonomous Calcium Signaling in Human and Zebrafish Podocytes Controls Kidney Filtration Barrier Morphogenesis

2021 ◽  
pp. ASN.2020101525
Author(s):  
Lydia Djenoune ◽  
Ritu Tomar ◽  
Aude Dorison ◽  
Irene Ghobrial ◽  
Heiko Schenk ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Calcium Release ◽  
Human Kidney ◽  
Calcium Transients ◽  
Filtration Barrier ◽  
Barrier Formation ◽  
Process Formation ◽  
Foot Process ◽  
Kidney Organoids

BackgroundPodocytes are critical to maintaining the glomerular filtration barrier, and mutations in nephrotic syndrome genes are known to affect podocyte calcium signaling. However, the role of calcium signaling during podocyte development remains unknown.MethodsWe undertook live imaging of calcium signaling in developing podocytes, using zebrafish larvae and human kidney organoids. To evaluate calcium signaling during development and in response to channel blockers and genetic defects, the calcium biosensor GCaMP6s was expressed in zebrafish podocytes. We used electron microscopy to evaluate filtration barrier formation in zebrafish, and Fluo-4 to detect calcium signals in differentiating podocytes in human kidney organoids.ResultsImmature zebrafish podocytes (2.5 days postfertilization) generated calcium transients that correlated with interactions with forming glomerular capillaries. Calcium transients persisted until 4 days postfertilization, and were absent after glomerular barrier formation was complete. We detected similar calcium transients in maturing human organoid glomeruli, suggesting a conserved mechanism. In both models, inhibitors of SERCA or IP3 receptor calcium-release channels blocked calcium transients in podocytes, whereas lanthanum was ineffective, indicating the calcium source is from intracellular podocyte endoplasmic-reticulum stores. Calcium transients were not affected by blocking heartbeat or by blocking development of endothelium or endoderm, and they persisted in isolated glomeruli, suggesting podocyte-autonomous calcium release. Inhibition of expression of phospholipase C-γ1, but not nephrin or phospholipase C-ε1, led to significantly decreased calcium activity. Finally, blocking calcium release affected glomerular shape and podocyte foot process formation, supporting the critical role of calcium signaling in glomerular morphogenesis.ConclusionsThese findings establish podocyte cell–autonomous calcium signaling as a prominent and evolutionarily conserved feature of podocyte differentiation and demonstrate its requirement for podocyte foot process formation.

539-P: The Trend of Diabetic Kidney Disease with Low eGFR and Absence of Albuminuria in Type 2 Diabetic Patients in Japan from 1996-2015

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 539-P
Author(s):  
YOSHINORI KAKUTANI ◽  
MASANORI EMOTO ◽  
KATSUHITO MORI ◽  
YUKO YAMAZAKI ◽  
AKINOBU OCHI ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Diabetic Kidney ◽  
Type 2 Diabetic

GENETIC ROLE OF HLA-G14 BASE PAIR INDEL POLYMORPHIC GENE WITH TYPE 1 DIABETIC PATIENTS

2019 ◽  
Vol 22 (09) ◽  
pp. 154-160
Author(s):  
Hasanain Khaleel Shareef ◽  
Ahmed Adil Ali ◽  
Rafah F. Al-Jebori
Keyword(s):  
Base Pair ◽  
Diabetic Patients ◽  
Polymorphic Gene ◽  
Type 1 Diabetic Patients

Role of Oxidative Stress and Mitochondrial Dysfunction in Skeletal Muscle in Type 2 Diabetic Patients

2016 ◽  
Vol 22 (18) ◽  
pp. 2650-2656 ◽  
Author(s):  
Noelia Diaz-Morales ◽  
Susana Rovira-Llopis ◽  
Irene Escribano-Lopez ◽  
Celia Bañuls ◽  
Sandra Lopez-Domenech ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Vol 20 ◽  
Author(s):  
Bipin Singh
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

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