Not too much, not too little-just the right amount: the story of YAP in the podocyte.

Chen et al. identify dysregulation of the transcriptional activator Yes-associated protein in the podocytes of diabetic mouse and human kidneys. Podocyte Yes-associated protein deficiency led to downregulation of the key transcription factor Wilms' tumor 1, and worsened podocyte injury in a mouse model of diabetic kidney injury.

Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females.

Humoral Responses in the Omicron Era Following 3-Dose SARS-CoV-2 Vaccine Series in Kidney Transplant Recipients.

Unlabelled: Kidney transplant recipients (KTRs) have a diminished response to SARS-CoV-2 vaccination compared with immunocompetent individuals. Deeper understanding of antibody responses in KTRs following third-dose vaccination would enable identification of those who remain unprotected against Omicron.

Methods: We profiled antibody responses in KTRs pre- and at 1 and 3 mo post-third-dose SARS-CoV-2 mRNA-based vaccine.

Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity.

Knowledge of the transcriptional programs underpinning the functions of human kidney cell populations at homeostasis is limited. We present a single-cell perspective of healthy human kidney from 19 living donors, with equal contribution from males and females, profiling the transcriptome of 27677 cells to map human kidney at high resolution. Sex-based differences in gene expression within proximal tubular cells were observed, specifically, increased anti-oxidant metallothionein genes in females and aerobic metabolism-related genes in males.

NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling.

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor-β (TGF-β)-driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear.

Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis.

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues.

Evaluation of a gene expression biomarker to identify operationally tolerant liver transplant recipients: the LITMUS trial.

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal.

Increased Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B in Patients With Kidney Allograft Antibody-mediated Rejection.

Unlabelled: Antibody-mediated rejection (AMR) causes more than 50% of late kidney graft losses. In addition to anti-human leukocyte antigen (HLA) donor-specific antibodies, antibodies against non-HLA antigens are also linked to AMR. Identifying key non-HLA antibodies will improve our understanding of AMR.

Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes.

Unlabelled: Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis.

Methods: Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation.

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis.

Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of donation after circulatory death injury compared with static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at three time points from pig kidneys subjected to 30 min of warm ischemia, followed by 8 h of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (false discovery rate < 0.

Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study.

Background: Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNF trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear.

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells.

Dysregulation of inflammatory responses is a hallmark of multiple diseases such as atherosclerosis and rheumatoid arthritis. As constitutively active transcription factors, NR4A nuclear receptors function to control the magnitude of inflammatory responses and in chronic inflammatory disease can be protective or pathogenic. Within this study, we demonstrate that TLR4 stimulation using the endotoxin lipopolysaccharide (LPS) rapidly enhances NR4A1-3 expression in human and murine, primary and immortalized myeloid cells with concomitant gene transcription and protein secretion of MIP-3α, a central chemokine implicated in numerous pathologies.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

Background And Objectives: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome.

Design, Setting, Participants, & Measurements: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases.

Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1.

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-β1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-β1 suppressed expression of let-7c.

The genetics of diabetic nephropathy.

Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN.