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| Open AccessVariants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
A vesicle trafficking Rab11 effector switch is important for ciliogenesis. Here, the authors report a ciliopathy-related disorder caused by variants in WDR44, a Rab11 effector. WDR44 variants show higher affinity for Rab11 and can impair ciliogenesis.
- Andrea Accogli
- , Saurabh Shakya
- & Christopher J. Westlake
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Article
| Open AccessPolygenic risk alters the penetrance of monogenic kidney disease
Polygenic factors may partially explain the observed variability in the penetrance of monogenic diseases. Here, the authors show that a polygenic risk score for chronic kidney disease is significantly associated with a higher risk of renal dysfunction in the two most common monogenic forms of kidney disease, suggesting that accounting for polygenic factors improves risk stratification in monogenic kidney disease.
- Atlas Khan
- , Ning Shang
- & Krzysztof Kiryluk
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| Open AccessFibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
- Rebecca V Walker
- , Qin Yao
- & Feng Qian
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Article
| Open AccessThe C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Mutations in the gene encoding PC1 cause ADPKD, a common genetic renal disease. Here, the authors show that expression of the C-terminal 200 amino acids of the large PC1 protein in mouse models of ADPKD suppresses cystic disease through an interaction with the mitochondrial enzyme NNT.
- Laura Onuchic
- , Valeria Padovano
- & Michael J. Caplan
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Article
| Open AccessGlucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules. Here the authors show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive pathway.
- Sienna R. Li
- , Ramila E. Gulieva
- & Benjamin S. Freedman
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| Open AccessDefining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Autosomal dominant polycystic kidney disease (ADPKD) is a complicated disease that involves numerous cell types. Here the authors used a multiomics approach consisting of single nucleus transcriptomes and epigenomes to redefine cell states in ADPKD and to dissect the cellular interactions and molecular mechanisms of ADPKD.
- Yoshiharu Muto
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open AccessPKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
- Ronak Lakhia
- , Harini Ramalingam
- & Vishal Patel
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Article
| Open AccessExtracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.
- Hao Ding
- , Linda Xiaoyan Li
- & Xiaogang Li
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Article
| Open AccessCyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo
Polycystic kidney disease (PKD) is characterized by the formation of large renal cysts, which lead to a decline in renal function. Here the authors show that genetic and chemical inhibition of TMEM16A largely reduces cyst enlargement in an in vivo model of autosomal dominant PKD.
- Ines Cabrita
- , Andre Kraus
- & Björn Buchholz
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Article
| Open AccessDiscovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.
- Edmund C. Lee
- , Tania Valencia
- & Vishal Patel
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Article
| Open AccessTMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells
Polycystin-2 (PC2) is an ion channel commonly found mutated in autosomal dominant polycystic kidney disease. Here Arhatte et al. identify transmembrane protein 33 (TMEM33) as a regulator of PC2 function at the endoplasmic reticulum, and find that deletion of TMEM33 protects mice from acute kidney injury.
- Malika Arhatte
- , Gihan S. Gunaratne
- & Amanda Patel
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Article
| Open AccessHydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels
Mutations in the cation channel PKD2 cause human autosomal dominant polycystic kidney disease but its channel function and gating mechanism are poorly understood. Here authors study PKD2 using electrophysiology and cryo-EM, which identifies hydrophobic gates and proposes a gating mechanism for PKD2.
- Wang Zheng
- , Xiaoyong Yang
- & Xing-Zhen Chen
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Article
| Open AccessLkb1 deficiency confers glutamine dependency in polycystic kidney disease
Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.
- Ebony M. Flowers
- , Jessica Sudderth
- & Thomas J. Carroll
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Article
| Open AccessmicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disease that leads to renal failure. Here Hajarniset al. show that miR-17 modulates cyst progression in ADPKD through metabolic reprogramming of mitochondria and its inhibition slows cyst development and improves renal functions.
- Sachin Hajarnis
- , Ronak Lakhia
- & Vishal Patel
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| Open AccessmTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex
Polycystic kidney disease (PKD) is a ciliopathy resulting from defective localization of membrane proteins such as PC-1 to the primary cilium, resulting in renal cysts, and is associated with another cystic genetic disease called tuberous sclerosis complex (TSC). Here the authors use kidney-specific Tsc1 and Pkd1 mice to show that mTORC1 signalling inhibits PC-1 biogenesis as a potential mechanism of TSC/PKD contiguous gene syndrome.
- Monika Pema
- , Luca Drusian
- & Alessandra Boletta
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Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis
Loss-of-function mutations in PKD1, the gene encoding the plasma membrane receptor Polycystin-1, lead to renal cyst formation in polycystic kidney disease. Here, Castelli et al. show that Polycystin-1 interacts with the Par3 polarity complex and has a role in the morphogenesis of kidney tubules during mouse development.
- Maddalena Castelli
- , Manila Boca
- & Alessandra Boletta
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Molecular mechanism of the assembly of an acid-sensing receptor ion channel complex
Polycystic kidney disease family proteins form heteromeric complexes with transient receptor potential channel subunits of the TRPP subfamily. Yu and colleagues find that the polycystic kidney disease protein, PKD1L3, is an ion channel pore-forming subunit in the acid-sensing PKD1L3/TRPP3 complex.
- Yong Yu
- , Maximilian H. Ulbrich
- & Jian Yang