Biomedical subjects

Matthias Kretzler

Publications and source records attributed to Matthias Kretzler.

5 recordsLinked to original sources

PubMed2026

FOXC2 and WT1 regulate transcriptional reprogramming during the podocyte response to injury.

Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.

Animals↗

PubMed2026

Single-cell profiling reveals epithelial and immune responses in BK polyomavirus-infected human kidney biopsies.

INTRODUCTIONBK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood.METHODSIn a cross-sectional study, single-cell RNA-seq from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and 2 distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction).RESULTSGenes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally, enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV-infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models, likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient-derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection.CONCLUSIONThese not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.

Humans↗

PubMed2026

Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant.

IMPORTANCE: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. OBJECTIVE: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. EXPOSURES: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. MAIN OUTCOME AND MEASURE: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). RESULTS: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. CONCLUSIONS AND RELEVANCE: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Humans↗

PubMed2026

Urinary clusterin as a biomarker of human kidney disease progression and response to the endothelin receptor antagonist atrasentan: An exploratory analysis from the SONAR trial.

The endothelin receptor antagonist atrasentan improved kidney outcomes in the SONAR trial for type 2 diabetes and chronic kidney disease (NCT01858532), though individual responses varied. To identify molecular biomarkers of atrasentan response and outcome, we conducted a nested case-control proteomics study (N = 180) within the SONAR trial population and identified urinary clusterin (uCLU) as the top candidate. Transcriptomic analyses of human kidney biopsies at tissue and single cell level from independent cohorts revealed higher CLU mRNA levels associated with worse kidney function and outcomes. An endothelin signaling activation score derived from pathway genes was reduced by atrasentan in mice with diabetic kidney disease. In the SONAR trial (N = 3,060) population, higher uCLU predicted worse outcomes, while atrasentan reduced uCLU by 42.6% over six weeks. Early uCLU changes independently predict improved kidney outcomes. In summary, uCLU is associated with kidney disease progression and response to atrasentan treatment, supporting its potential as a pharmacodynamic biomarker to target therapy.

Humans↗

PubMed2025

Liquid Biopsy-Multiomics Link Adhesion Pathway Dysregulation to Kidney Injury Severity.

INTRODUCTION: Severe acute kidney injury (AKI) is strongly associated with the risk of developing chronic kidney disease; however, little is known about the cell type-specific mechanisms driving kidney injury severity. METHODS: In this multicenter observational study, we used clinically obtained liquid biopsy proteomics and machine learning (ML) to predict severe outcomes in patients with COVID-associated and non-COVID AKI. Further, we orthogonally combined 169 urine proteomics with 437 plasma proteomics samples and 40 urine sediment single-cell transcriptomics samples to identify complementary dysregulated mechanisms. RESULTS: Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrate predictive power for both discovery and validation set with AUC of 87% and 76%, respectively. These predictive proteomics features obtained demonstrate that cell adhesion and autophagy-associated pathways are uniquely impacted in severe AKI. Differentially abundant proteins (DAPSs) associated with these pathways are highly expressed in cells of the juxtamedullary nephron, endothelial cells (ECs), and podocytes, indicating that these kidney cell types could be potential targets. Single-cell transcriptomic analysis in the in vitro model of kidney organoids infected with SARS-CoV-2 reveal dysregulation of extracellular matrix (ECM) organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters shows significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. CONCLUSION: Collectively, these data suggest that ECM degradation and adhesion-associated mechanisms could be the main driver of severe kidney injury.

AKI↗