Nek8 Regulates the Expression and Localization of Polycystin-1 and Polycystin-2

Sohara, Eisei; Luo, Ying; Zhang, Jingjing; Manning, Danielle K.; Beier, David R.; Zhou, Jing

doi:10.1681/asn.2006090985

Cited by 113 publications

(103 citation statements)

References 37 publications

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“…(76) Finally, the underlying defect in jck mice is due to activating mutations in Nek8, a gene encoding a serine protease kinase that promotes protein trafficking of two cilia-associated proteins, polycystin 1 and 2 (PC1 and PC2). (77) Activating Nek8 mutations lead to increased primary cilia length in the kidney, (28,77) whereas loss of function mutations in PKD1 induce PKD, skeletal defects in vivo, and decreased osteoblast differentiation in vitro. (78,79) As primary cilia may be part of the mechanosensing machinery that influences bone remodeling via b-catenin signaling, (80) NEK8 mutations in jck could theoretically influence the onset of HTO bone disease.…”

Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

237

224

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

237

224

View full text Add to dashboard Cite

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“…11,[16][17][18][19][20][21] Therefore, we examined the ciliary length of proximal tubules in AQP11(2 /2 ) mice. Elongated primary cilia of proximal tubules were observed in AQP11(2/2) mice ( Figure 9).…”

Section: Aqp11 Localizes To Er In Vivomentioning

confidence: 99%

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

Inoue

Sohara

Kobayashi

et al. 2014

Journal of the American Society of Nephrology

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We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(2/2) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg AQP11 )that express 33HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg AQP11 mice and rescued renal cystogenesis in AQP11(2/2) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(2/2) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(2/2) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/2) background increased the severity of cystogenesis in AQP11(2/2) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(2/2) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(2/2) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(2/2) mice could be a key mechanism of cystogenesis in AQP11(2/2) mice.

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“…2 Nek kinases function in the formation of the primary cilium in many eukaryotes. [3][4][5][6][7][8] They also play roles in DNA repair 9 and apoptosis. 10 Spontaneous mutations in genes encoding two members of the Nek family give rise to autosomal recessive forms of polycystic kidney disease (PKD) in the mouse.…”

mentioning

confidence: 99%

“…18,19 Nek8 has not been shown thus far to be catalytically active. Nek8 nevertheless regulates the expression and localization of the polycystins 4,20 and has been linked to medullary cystic kidney disease (nephronopthisis). 8 Knockdown of Nek8 in zebrafish embryos results in cystic kidney.…”

mentioning

confidence: 99%