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Low nephron endowment constitutes a risk factor for hypertension and renal disease. Epigenetic regulation is crucial for nephron progenitor cell differentiation, affecting nephron number and renal function. The role of many epigenetic modulators, such as Lysine-specific histone demethylase 1a (LSD1 or KDM1A), remains unclear. We used Kdm1a-KO mice to demonstrate that Kdm1a depletion in nephron progenitor cells results in reduced kidney size in neonates and led to glomerulosclerosis, proteinuria, and renal cysts in adults. Notably, Kdm1a deletion in podocytes or tubular cells did not replicate these effects. CRISPR/Cas9-mediated KDM1A deletion in human kidney organoids caused cyst formation and altered gene expression, with snRNA-seq revealing downregulation of podocyte genes and upregulation of metabolic genes. The presence of noncoding RNAs indicated roles in cell proliferation. Our study reveals the critical role of Kdm1a function in nephron development and highlights its affect on transcriptional programming for long-term renal function and susceptibility to cyst formation.

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Aberrant neutrophil (PMN) accumulation in the tissue induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and 'do not eat me' signals due to impaired synthesis of the deubiquitinase, A20. Decreased A20 levels, in turn, activated the transcription factor NFκB and the secretion of MIP2α (human homolog of IL8) in ECs. EC-secreted MIP2α/IL8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in EC or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg-/- mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC-Erg-A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN-CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with pro-inflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into four experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA sequencing. Histology revealed increased renal infiltration of CD4⁺/CD8⁺ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA sequencing revealed shifts in immune cell populations and genes of interest including: Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and pro-inflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.

Background: High-dose influenza vaccine, containing four times more antigen than standard-dose, is recommended for people aged ≥ 65 years, but there is a knowledge gap surrounding its effect in people with HIV (PWH), who remain more vulnerable to serious influenza infections than people without HIV (PWoH) despite virological suppression. The primary goal of this study was to assess whether high-dose improves antibody responses in PWH, with a particular focus on older PWH.

Methods: We conducted a study to assess antibody responses to sequential high- versus standard-dose influenza vaccination in PWH. Young (18-40 years) PWoH (n=55) and PWH (n=37); and older (≥ 60 years) PWoH (n=72) and PWH (n=67) received standard-dose during the 2020-2024 seasons and 123 participants, including 41 older PWH, received high-dose the consecutive season. All PWH were virologically suppressed on ART. Hemagglutination inhibition (HAI) titer and HA-specific IgG were analyzed at 0- to 180-days post-vaccination (dpv); T cell activation-induced responses were assessed by flow cytometry.

Results: All groups mounted significant HAI and IgG responses to all vaccine antigens at 28 dpv, after standard- and high-dose vaccination. Responses to A/H1N1 were lower in magnitude and durability in older PWH compared to young PWoH following standard-dose and were not boosted with high-dose, whereas high-dose enhanced A/H3N2 and B/Victoria IgG, and CD4+ T cell responses to all antigens, in older PWH.

Conclusion: Our data demonstrate partial efficacy of high-dose in augmenting antibody responses of older PWH while highlighting limitations in boosting A/H1N1-specific responses.

Trial registration:

Clinicaltrials: gov NCT04487041.

Funding: NIH grant (5R01AG068110).

GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose, but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and pro-apoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in pre-constricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.

Insulin and glucagon are described to have opposing actions on hepatic glycogen metabolism. However, here we showed that their coordinated action promoted glycogen turnover and meal glucose storage. In mice, pharmacological doses of insulin or glucagon failed to alter hepatic glycogen, but the combination produced a robust decrease in glycogen content. Additivity between insulin and glucagon was also seen with the activation of hepatic insulin signaling intermediates. This signaling pathway drove glycogen synthesis, suggesting concurrent actions on glycogen breakdown and repletion. A mixed nutrient meal, which stimulates an increase in both insulin and glucagon, enhanced the incorporation of dietary glucose into hepatic glycogen. This was much more pronounced than the effects of glucose alone, which only stimulated insulin secretion. These findings revealed that glucagon is required for efficient hepatic glucose storage when acting in concert with insulin. Coordinated insulin-glucagon signaling thus emerged as a critical mechanism for hepatic glycogen cycling, challenging the classical paradigm that these hormones work in opposition.

This study provides a comprehensive evaluation of the cutaneous adipose tissue (CAT) transcriptome in psoriasis patients and investigates the effects of IL-17 blockade on CAT inflammation through a randomized placebo-controlled trial using secukinumab (ObePso-S study, NCT03055494). RNA sequencing analysis of CAT biopsies from 82 psoriasis patients revealed 2132 differentially expressed transcripts compared to healthy controls. Notably, significant gene dysregulation was observed in both lesional skin (LS)- and non-lesional (NL)-CAT, including activation of IL-17-driven pathways, antimicrobial peptide-related, and neutrophil degranulation signatures. Stratification by obesity demonstrated that obese psoriatic CAT exhibited more than 2-fold higher number of differentially expressed genes than non-obese counterparts, suggesting a synergistic interaction between psoriasis and obesity in driving CAT inflammation. Treatment with secukinumab markedly improved inflammatory signatures in psoriatic CAT, with greater improvements observed in obese patients. These findings reveal a pronounced and partially dependent on IL-17-dependent inflammatory phenotype in psoriatic CAT, challenge the conventional concept of psoriasis as a solely superficial skin disease, and highlight CAT as an important contributor to systemic inflammation in psoriasis.

Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using whole-body and cardiomyocyte-specific TIGAR knockout mice, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin-dependent, as double knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increased Parkin expression in multiple cell lines. Our findings reveiled how early cardiac metabolism programmed lifelong cardiac function through epigenetic mechanisms, and identifyied developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.

While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a-/-) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a-/- mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.