Biology subjects

Viau, A.

Publications and source records attributed to Viau, A..

9 recordsLinked to original sources

bioRxiv2026

Developmental switch dichotomizes kidney response to NPHP3 inactivation and treatment outcome

Nephronophthisis (NPH) is n rare recessive kidney disease caused by biallelic variants in more than 25 NPHP genes encoding proteins that localize to primary cilia. It is characterized by three different forms depending on the age of onset and kidney lesions: infantile (cystic), juvenile/late onset (fibrotic). To date, the pathways linking altered primary cilia function to progressive kidney scarring in NPH remain poorly defined and therapeutic options are lacking. To address these questions, we generated two new mouse NPH models by inactivating Nphp3 specifically in kidney tubules either during embryogenesis or in adult, recapitulating the infantile and juvenile forms of the disease, respectively. Embryonic inactivation produced a rapid and severe cystic phenotype with tubular dedifferentiation, progressive interstitial fibrosis, inflammation and kidney failure, while postnatal inactivation led to a slowly progressive tubulointerstitial nephropathy characterized by tubular atrophy, fibrosis and immune cell infiltration without cyst formation. Strikingly, cilia were preserved in the early stages of both models, indicating that ciliogenesis impairment is not a primary driver of NPH3 pathogenesis. Transcriptomic profiling of the juvenile model revealed that disease initiation is driven by mitochondrial dysfunction, innate immune activation and aberrant cell cycle progression, while epithelial-to-mesenchymal transition and Wnt/{beta}-catenin remodelling emerges only at later stages of disease progression. Therapeutic intervention with the PGE1 (alprostadil) failed to rescue the cystic/infantile model but significantly attenuated fibrosis, inflammation and interstitial fibrosis in the fibrotic/juvenile model. The ability to recapitulate both disease forms through temporal modulation of gene inactivation suggests that primary cilia serve distinct, stage-specific functions in kidney tubular homeostasis, with different cellular processes being selectively vulnerable depending on the causative gene or variant. Collectively, these findings uncover early pathogenic mechanisms that may constitute tractable therapeutic targets for the treatment of nephronophthisis.

pathology↗

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

Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

BackgroundWhile pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. ObjectiveWe investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. DesignWe analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. ResultsMutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with HNF1B and NPHP3 mutations. ConclusionWe describe a previously unrecognized pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft. What is already known on this topicO_LICiliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. C_LIO_LIPancreatic cysts have been sporadically reported in syndromic ciliopathies. C_LIO_LIThe pancreas is not currently recognized as a major target organ of ciliary dysfunction. C_LIO_LIA clear link between ciliary gene mutations and pancreatic anomalies is still unknown. C_LIO_LIAnimal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. C_LI What this study addsO_LIIdentifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). C_LIO_LIDemonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. C_LIO_LIReveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. C_LIO_LIShows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. C_LIO_LIDefines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. C_LI How this study might affect research, practice or policyO_LIEstablishes the pancreas as a novel and clinically relevant target of ciliopathies. C_LIO_LIExpands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. C_LIO_LISuggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. C_LIO_LIHighlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. C_LIO_LIOpens new research avenues into the role of primary cilia in pancreatic homeostasis and disease. C_LI

cell biology↗

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

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator of NPHP1 ciliopathy gene transcripts

Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novel ANKS3 variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of the ANKS3 mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation of ANKS3. Finally, our results evidenced that these classically renal ciliopathy-associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH gene NPHP1 and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator of NPHP1 transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.

pathology↗

bioRxiv2022

Prostaglandin E1 as therapeutic molecule for Nephronophthisis and related ciliopathies

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using an in cellulo medium-throughput drug-screen, we identified 51 FDA-approved compounds and selected 11 for their physicochemical properties, including prostaglandin E1 (PGE1). PGE1 was further validated to rescue ciliogenesis in immortalized patient NPHP1-/- urine-derived renal tubular cells and corroborated by the effects of its analog PGE2. The two molecules reduced pronephric cyst occurrence in vivo in nphp4 zebrafish model, and PGE1 treatment in Nphp1-/- mice led to a significant reduction of renal tubular dilatations, partially restoring cilia length within tubules. Finally, comparative transcriptomics allowed identification of key molecules downstream PGE1. Altogether, our drug-screen strategy led to the identification of PGE1 as the first potential therapeutic molecule for NPH-associated ciliopathies. Significant statementJuvenile nephronophthisis (NPH) is a renal ciliopathy due to a dysfunction of primary cilia and a common genetic cause of end-stage renal disease in children and young adults. No curative treatment is available. This paper describes the identification of Prostaglandin E1 (PGE1) as the first potential therapeutic molecule for NPH-associated ciliopathies. We demonstrated that PGE1 rescues defective ciliogenesis and ciliary composition in NPHP1-/- patient urine-derived renal tubular cells. Furthermore, PGE1 improves ciliary and kidney phenotypes in our NPH zebrafish and Nphp1-/- mouse models. Finally, in vitro experiments as well as transcriptomic analyses pointed out several pathways downstream PGE1 as cAMP, cell-cell/cell-matrix adhesion or actin cytoskeleton. Altogether, our findings provide a new alternative for treatment of NPH.

cell biology↗

bioRxiv2022

YAP restricts renal inflammation and mitigates kidney damage in nephronothisis related kidney disease.

Nephronophthisis (NPH) is an orphan recessive kidney disease mostly caused by mutations in NPHP1 and 20 other genes encoding proteins that localize to primary cilia. To date the pathways linking altered primary cilia function to progressive kidney scarring in NPH remain poorly defined and therapeutic options allowing NPH patients to escape end-stage kidney disease are lacking. Distinct proteins mutated in NPH interact with components of the Hippo pathway, an important regulator of cell fate. YAP (Yes-associated protein) overactivation has been shown to induce renal scarring while YAP inhibition showed protective effect in kidney diseases unrelated to NPH. Yet, the therapeutic potential of YAP inhibition in NPH has not been formerly assessed. Here we studied the impact of both genetic and pharmacologic YAP inhibition on the NPH-like phenotype caused by a bi-allelic mutation of Lkb1, a ciliary kinase interacting with NPHP1. Contrary to non NPH renal disease, our results reveal an unexpected protective role of YAP in Lkb1 mutant kidneys. Indeed, YAP genetic disruption drastically increase kidney disease burden in Lkb1 deficient mice, while pharmacologic inhibition of YAP failed to improve their phenotype. Collectively these results suggest that YAP inhibition is not a valid therapeutic strategy in NPH and suggest that LKB1 and YAP are parallel negative regulators of a yet uncharacterized pathway detrimental for kidney health.

pathology↗

bioRxiv2021

The renal inflammatory network of nephronophthisis.

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSThe majority of genetic kidney disease leading to kidney failure is caused by mutations in ciliary genes. How cilia malfunction leads to progressive kidney damage is poorly understood, but recent evidence links ciliopathy genes to CCL2 dependent macrophage recruitment in autosomal dominant polycystic kidney disease (ADPKD), the most studied renal ciliopathy. Whether or not renal inflammation is involved in other renal ciliopathies is unclear. METHODSWe combined mice models with kidney biopsies and renal epithelial cells sampled from human urine to characterize the renal inflammatory network of nephronophthisis (NPH), the most frequent renal ciliopathy in children. RESULTSIn human, mutations in cilia genes involved in NPH enhance urine excretion of the chemokine CCL2, causing abnormal macrophage recruitment in kidney tissues from NPH patients. Differing from ADPKD, inactivating Ccl2 specifically in mouse tubular cells does not rescue the NPH phenotype, suggesting that other inflammatory mediators are involved. Using transcriptional data from 2 NPH models, we identify a set of pro-inflammatory cytokines upregulated in this disease, independently of CCL2. The majority of detectable transcripts from this set are specifically upregulated in kidney cells from NPH patients. In line with the function of these cytokines, NPH kidneys show disproportionate neutrophils and T cells infiltrates compared to healthy subject or hypertensive and diabetic chronic kidney disease patients. CONCLUSIONSThis study reveals that inflammation is a central aspect in human NPH and delineates a specific set of inflammatory mediators that regulates immune cell recruitment in human NPH. SIGNIFICANCE STATEMENTMutations in genes encoding primary cilia proteins are the leading cause of genetic kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), deregulated cilia signaling leads to kidney infiltration by macrophages through the chemokine CCL2. Little is known about renal inflammation in nephronophthisis (NPH), the most frequent pediatric renal ciliopathy. Using NPH mice models, tissues and cells from NPH patients, we unveil renal inflammation as preeminent feature of NPH. Remarkably, the renal inflammatory evoked by ciliary gene mutations in NPH does not overlap with ADPKD: it is CCL2 independent, involves a prominent recruitment of neutrophils and T cells and a specific cytokine signature. This unforeseen findings strengthen the link between primary cilia and renal inflammation.

physiology↗

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↗