Biology subjects

Poree, E.

Publications and source records attributed to Poree, E..

5 recordsLinked to original sources

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↗

bioRxiv2025

Evaluation of Prostaglandin Receptor Agonists and Eupatilin in the Context of Nephronophthisis

BackgroundPrimary cilia are sensory antennas that are present on the majority of quiescent vertebrate cells where they mediate key signaling during development and in response to environmental stimuli. Defects in primary cilia result in a group of heterogeneous inherited disorders with overlapping phenotypes, called ciliopathies. Nephronophthisis is an autosomal recessive tubulo-interstitial kidney ciliopathy with more than 25 identified genes called NPHP. Presently, no treatment exists beyond supportive care and kidney transplant, underscoring the need for novel therapies. MethodsUsing a phenotypic screening approach in cultured cell lines, we previously identified prostaglandin analogues as candidate therapeutic molecules based on their ability to rescue ciliogenesis defects in kidney tubular cells from NPHP1 patients. Here, we have investigated the potential beneficial effects of ROCK inhibitors and Eupatilin, similarly identified by other groups in different NPHP contexts, in kidney cells from NPHP1 and IQCB1/NPHP5 patients as well as in a zebrafish NPHP mutant line (traf3ip1/ift54). ResultsEupatilin partially rescued NPHP1-associated ciliogenesis defects. Transcriptomic analyses pointed out that cell cycle progression was inhibited by Eupatilin, likely explaining its broad effects on cilia assembly. Interestingly, while ciliary defects also observed in NPHP5 patient cells were rescued by both prostaglandins and Eupatilin, only prostaglandin analogues were able to reduce pronephric cysts size in the used nphp zebrafish model. ConclusionOur study indicates that these molecules can show beneficial effects across genetic contexts and shed light on their potential as therapeutic interventions for nephronophthisis.

cell biology↗

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↗