Biology subjects

Terzi, F.

Publications and source records attributed to Terzi, F..

7 recordsLinked to original sources

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗

bioRxiv2026

Non-HLA antibodies worsen the histological phenotype and prognosis of antibody mediated rejection in kidney allografts

IntroductionAntibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure, with both HLA and non-HLA antibodies implicated in its pathogenesis. The contribution of non-HLA antibodies (non-HLA Abs) to microvascular inflammation (MVI) and graft outcome, particularly in cases lacking donor-specific anti-HLA antibodies (HLA-DSAs), remains incompletely understood. MethodsWe analyzed 571 post-transplant serum samples from 326 patients with histological features of AMR (AMRh) and 164 stable controls. Non-HLA Abs were detected using the previously developed Non-HLA Antibody Detection Immunoassay (NHADIA), and associations were examined with histological lesions, AMRh persistence, and graft outcomes. Biopsies were scored according to Banff 2022 criteria, and patients were stratified by HLA-DSA and NHADIA status. ResultsNHADIA values were significantly higher in AMRh patients compared to controls (P=0.0001), regardless of HLA-DSA status. NHADIA values correlated with the severity of glomerulitis, peritubular capillaritis and global MVI scores. In AMRh patients with HLA-DSAs, non-HLA Abs remained independently associated with MVI severity. Follow-up biopsies revealed persistent AMR lesions in patients with both HLA-DSAs and non-HLA Abs. Allograft survival was lowest in double-positive patients, and NHADIA positivity independently predicted graft loss (HR=2.25, 95% CI: 1.03-4.92, P=0.042). Incorporating NHADIA into the Banff classification reclassified 61% of AMRh cases as "double-positive AMRh," and identified new subgroups with significant prognostic differences. ConclusionPost-transplant detection of non-HLA antibodies identifies a distinct subset of AMR with more severe histology and worse graft prognosis, particularly when coexisting with HLA-DSAs. Integrating non-HLA Ab testing into current diagnostic frameworks may refine AMR classification and improve risk stratification. TRANSLATIONAL STATEMENTThis study highlights the clinical relevance of non-HLA antibodies, identified using our innovative endothelial cell-based assay (NHADIA), in kidney transplant recipients. Their presence is associated with more severe antibody-mediated rejection (AMR) and poorer graft outcomes, even in the absence of donor-specific HLA antibodies. Incorporating non-HLA antibody detection into routine post-transplant evaluation may allow clinicians to better identify high-risk patients, including those previously classified as DSA-negative AMR. This expanded immunological profiling refines AMR diagnosis, improves risk stratification, and opens new avenues for personalized immunosuppressive strategies, ultimately enhancing long-term graft survival and patient care.

pathology↗

bioRxiv2024

Cilia to basement membrane signalling is a biomechanical driver of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD), which affects around 4 million patients worldwide, is characterized by the formation of multiple tubule derived cysts, which grossly enlarge both kidneys and progressively compromise renal function. ADPKD mainly results from mutations in PKD1, leading to the loss of polycystin-1 protein, which localizes to primary cilia. Primary cilia are required for cyst formation but the biomechanical changes underlying cystogenesis upon loss of polycytin-1 are unknown. We find that cilia and polycystin-1 shape the tubular basement membrane (TBM). Combining orthologous mouse models with a tubule-on-chip approach allowing manipulations of TBM stiffness, we find that cilia regulate the composition and biomechanical properties of the TBM. In the setting of polycytin-1 loss, reduced TBM stiffness and increased luminal pressure act as biomechanical drivers of cyst formation. These findings suggest a novel biomechanical model for ADPKD and unveil that cilia to TBM signalling controls kidney shape.

physiology↗

bioRxiv2024

Lcn2 protects from cisplatin induced AKI by regulating DNA damage response via EGFR activation

BackgroundLipocalin 2 (Lcn2), a small-secreted protein, is an established sensitive biomarker of kidney injury. In Cisplatin (CDDP) induced acute kidney injury (AKI), Lcn2 expression is swiftly and strongly increased in suffering renal medullary tubules. While recent reports correlates Lcn2 expression in cancer cells with CDDP resistance, the role of Lcn2 in kidney tubule damaged by CDDP remains unknown. MethodsTo better understand the role of Lcn2 in CDDP-induced AKI, experiments on Lcn2+/+ or Lcn2-/- mice as well as immortalized kidney cells knock-down (KD) for Lcn2 were conducted. Kidney function and injury were assessed using standard techniques. Cellular and molecular mechanisms were studied in WT and Lcn2 KD cells in combination with pathways inhibitors in order to gain insight Lcn2 driven mechanisms. ResultsIn animal injected with CDDP, Lcn2 was upregulated mostly in kidney inner medulla collecting duct while it was reabsorbed in the proximal tubules. Lcn2-/- in mice significantly decreased kidney function compare to WT mice, while it increased parenchymal damage due to increased cell death and cast formation. Interestingly, while little to no damage were present in the medulla of CDDP injected WT animal, a clear increase of medulla tubular lesions was observed in Lcn2-/- mice. Using Inner Medullary Collecting Duct cells (mIMDC-3), we showed that Lcn2 KD induces a p53-dependent apoptosis upon Cisplatin exposure while no effect on necrosis was observed. Finally, we demonstrated that Lcn2 drives CDDP resistance to apoptosis through the activation of the pro-survival EGFR pathway. ConclusionsWe established that Lcn2 is a renoprotective protein in CDDP-induced AKI via the activation of EGFR pathway. This new mechanism might represent a new approach for the treatment of AKI.

cell biology↗

bioRxiv2023

YAP-dependent autophagy is controlled by AMPK, SIRT1 and flow intensity in kidney epithelial cells.

Shear stress generated by the urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow. Here, we show that nuclear YAP/TAZ negatively regulates autophagy machinery in kidney epithelial cells subjected to fluid flow. This crosstalk is supported by a primary cilium-dependent activation of AMPK and SIRT1, independently of the Hippo pathway. We confirmed the relevance of the YAP/TAZ-autophagy molecular dialog in vivo using a zebrafish model of kidney development and a unilateral ureteral obstruction mouse model. In addition, an in vitro assay simulating the pathological flow observed at early stages of chronic kidney disease (CKD) activated YAP, leading to a primary cilium-dependent inhibition of autophagy. Our findings demonstrate the importance of YAP/TAZ and autophagy in the translation of fluid flow into cellular and physiological responses. Dysregulation of this pathway is associated with the early onset of CKD.

cell biology↗

bioRxiv2021

Genetic engineering for in vivo optical interrogation of neuronal responses to cell type-specific silencing

Genetic engineering of quintuple transgenic brain tissue was used to establish a low background, Cre-dependent version of the inducible Tet-On system for fast, cell type-specific transgene expression in vivo. Co-expression of a constitutive, Cre-dependent fluorescent marker selectively allowed single cell analyses before and after inducible, tet-dependent transgene expression. Here, we used this method for acute, high-resolution manipulation of neuronal activity in the living brain. Single induction of the potassium channel Kir2.1 produced cell type-specific silencing within hours that lasted for at least three days. Longitudinal in vivo imaging of spontaneous calcium transients and neuronal morphology demonstrated that prolonged silencing did not alter spine densities or synaptic input strength. Furthermore, selective induction of Kir2.1 in parvalbumin interneurons increased the activity of surrounding neurons in a distance-dependent manner. This high-resolution, inducible interference and interval imaging of individual cells (high I5, HighFive) method thus allows visualizing temporally precise, genetic perturbations of defined cells.

neuroscience↗

bioRxiv2019

Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

The inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

pathology↗