An <i>Nphp1</i> knockout mouse model targeting exon 2–20 demonstrates characteristic phenotypes of human nephronophthisis

Dantong, Li; Hu, Miaoyue; Chen, Huamu; Wu, Xiaohong; Wei, Xiaoyi; Lin, Hsin-Fu; Gao, Xuefei; Wang, Haiyan; Li, Min; Ong, Albert; Yue, Zhihui; Sun, Liangzhong

doi:10.1093/hmg/ddab239

Cited by 12 publications

(13 citation statements)

References 58 publications

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“…Genetic interactions between genes for ADPKD and syndromic forms of PKD, including NPHP and Joubert Syndrome have been hampered due to the lack of mouse models faithfully recapitulating NPHP or the renal phenotype of Joubert syndrome patients. In most NPHP types, especially in juvenile-adult types, and Joubert syndrome mouse models, renal function does not deteriorate as fast as seen in patients 25–28 . Our Cdh16Cre;Fbxw7 f/f mice faithfully recapitulated juvenile-adult NPHP, allowing us to test genetic interactions with ADPKD genes.…”

Section: Resultsmentioning

confidence: 95%

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Patel,

Gerakopoulos,

Petsouki

et al. 2024

Preprint

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Nephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deleting Fbxw7 encoding FBW7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion of Fbxw7 in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.

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Section: Resultsmentioning

confidence: 95%

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Patel,

Gerakopoulos,

Petsouki

et al. 2024

Preprint

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“…To validate the deleterious effect of the selected mutations at cellular level, we first analyzed ciliogenesis, known to be altered in other NPHP model ( Delous et al, 2009 ; Burcklé et al, 2011 ; Vincensini et al, 2011 ; Li et al, 2021 ; Garcia et al, 2022 ). No change of percentage of ciliated cells was observed; however, cilium length was increased in KD_N1 and KD_N4 cell lines ( Figures 1D–D” ).…”

Section: Resultsmentioning

confidence: 99%

Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4

Garfa Traoré,

Roccio,

Miceli

et al. 2023

Front. Mol. Biosci.

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Renal epithelial cells are subjected to fluid shear stress of urine flow. Several cellular structures act as mechanosensors–the primary cilium, microvilli and cell adhesion complexes–that directly relay signals to the cytoskeleton to regulate various processes including cell differentiation and renal cell functions. Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy leading to end-stage kidney failure before adulthood. NPHP1 and NPHP4 are the major genes which code for proteins that form a complex at the transition zone of the primary cilium, a crucial region required for the maintenance of the ciliary composition integrity. These two proteins also interact with signaling components and proteins associated with the actin cytoskeleton at cell junctions. Due to their specific subcellular localization, we wondered whether NPHP1 and NPHP4 could ensure mechanosensory functions. Using a microfluidic set up, we showed that murine inner medullary collecting ductal cells invalidated for Nphp1 or Nphp4 are more responsive to immediate shear exposure with a fast calcium influx, and upon a prolonged shear condition, an inability to properly regulate cilium length and actin cytoskeleton remodeling. Following a transcriptomic study highlighting shear stress-induced gene expression changes, we showed that prolonged shear triggers both cholesterol biosynthesis pathway and uptake, processes that do not seem to involve neither NPHP1 nor NPHP4. To conclude, our study allowed us to determine a moderate role of NPHP1 and NPHP4 in flow sensation, and to highlight a new signaling pathway induced by shear stress, the cholesterol biosynthesis and uptake pathways, which would allow cells to cope with mechanical stress by strengthening their plasma membrane through the supply of cholesterol.

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“…One of the main difficulty faced studying the pathophysiologic events driving kidney damage in NPH is the overall lack of orthologous rodent models recapitulating all the disease features. Indeed, Nphp1 inactivation does not lead to significant kidney fibrosis 5,6 in mice and the same is true for the majority of NPH genes. One notable exception is Glis2 , which inactivation consistently leads to kidney fibrosis in mice 7,8 , but accounts for only 0.1% of NPH cases in human.…”

Section: Introductionmentioning

confidence: 80%

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

Ferri¹,

Goffette²,

Poree³

et al. 2022

Preprint

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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.

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An Nphp1 knockout mouse model targeting exon 2–20 demonstrates characteristic phenotypes of human nephronophthisis

Cited by 12 publications

References 58 publications

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4

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

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