Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease

Torres, Vicente E.; Wang, Xiaofang; Qian, Qi; Somlo, Stefan; Harris, Peter C.; Gattone, Vincent H.

doi:10.1038/nm1004

Cited by 442 publications

(344 citation statements)

References 12 publications

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“…Recent reports have shown that the same chemical molecule (a vasopressin V2 receptor antagonist, OPC31260) can inhibit cyst progression in both a rat genetic model of ARPKD and a mouse genetic model of ADPKD, suggesting that both causal gene products for AD-PKD and ARPKD may reside in a common molecular pathway. 42 Recently, our company study demonstrated that FPC and PC2 indirectly interact via their COOH-termini and that this is mediated by KIF3B, a motor subunit of the heterotrimer kinesin-2. 36 Pkd2-channel activities were significantly altered when the FPC-PC2 complex was disrupted.…”

Section: Discussionmentioning

confidence: 99%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway. For investigation of this, a mouse model with a gene-targeted mutation in Pkhd1 that recapitulates phenotypic characteristics of human autosomal recessive polycystic kidney disease was produced. The absence of FPC is associated with aberrant ciliogenesis in the kidneys of Pkhd1-deficient mice. It was found that the COOH-terminus of FPC and the NH2-terminus of PC2 interact and that lack of FPC reduced PC2 expression but not vice versa, suggesting that PC2 may function immediately downstream of FPC in vivo. PC2-channel activities were dysregulated in cultured renal epithelial cells derived from Pkhd1 mutant mice, further supporting that both cystoproteins function in a common pathway. In addition, mice with mutations in both Pkhd1 and Pkd2 had a more severe renal cystic phenotype than mice with single mutations, suggesting that FPC acts as a genetic modifier for disease severity in autosomal dominant polycystic kidney disease that results from Pkd2 mutations. It is concluded that a functional and molecular interaction exists between FPC and PC2 in vivo.

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Section: Discussionmentioning

confidence: 99%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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“…Mozavaptan is a selective vasopressin-2 receptor antagonist that decreases renal cAMP levels and attenuates cyst growth. 17 qPCR analysis revealed that the expression of primiR-21 was reduced by approximately 30% (P=0.03) and that the expression of mature miR-21 transcripts was reduced by 50% (P=0.01) in kidneys of mozavaptan-treated Pkd2 2/WS25 mice compared with vehicle-treated Pkd2 2/WS25 mice ( Figure 2, I and J). Consistent with the notion that cAMP signaling regulates miR-21 independent of its host gene Vmp1, mozavaptan treatment did not affect Vmp1 expression.…”

Section: Mir-21 Is Upregulated In Pkdmentioning

confidence: 99%

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

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“…However, if we assume that the primary defect in type 2 ADPKD is PKD2-mediated Ca 2+ influx (and not Na + or K + which also pass through PKD2), it is possible that a connection between a Ca 2+ channel and cAMP can be made. It has been reported that cystic cells have abnormally high levels of cAMP [79][80][81][82] and the administration of a vasopressin V2 receptor antagonist, which reduced cAMP, suppressed the cystic phenotype in PKD2 knock out mice [83] and other animal models [84,85]. It is also known that store-operated Ca 2+ channels are directly coupled to specific isoforms of adenylyl cyclases [86][87][88].…”

Section: Pkd2-mediated Signal Transductionmentioning

confidence: 99%

Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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Naturally occurring mutations in two separate, but interacting loci, pkd1 and pkd2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases resulting primarily in the formation of large kidney, liver, and pancreatic cysts. Homozygous deletion of either pkd1 or pkd2 results in embryonic lethality in mice due to kidney and heart defects illustrating their indispensable roles in mammalian development. However, the mechanism by which mutations in these genes cause ADPKD and other developmental defects are unknown. Research in the past several years has revealed that PKD2 has multiple functions depending on its subcellular localization. It forms a receptor-operated, non-selective cation channel in the plasma membrane, a novel intracellular Ca 2+ release channel in the endoplasmic reticulum (ER), and a mechanosensitive channel in the primary cilium. This review focuses on the functional compartmentalization of PKD2, its modes of activation, and PKD2-mediated signal transduction.

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Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease

Cited by 442 publications

References 12 publications

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Cell biology of polycystin-2

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