Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Nagy, Irina I.; Xu, Qi; Naillat, Florence; Ali, Nsrein; Miinalainen, Ilkka; Samoylenko, Anatoly; Vainio, Seppo

doi:10.1186/s12861-016-0131-z

Cited by 22 publications

(31 citation statements)

References 48 publications

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“…Wnt’s have been proposed as directional signals in Drosophila [25] and in vertebrates[18], though their ability to act as instructive signals is not firmly established. Several Wnt’s required for kidney development[8, 13, 27, 28] should be considered as candidate directional cues. The requirement of Fat4 and Dchs1 for normal OCD suggests the possibility that these provide a directional cue analogous to that proposed for Drosophila Ft-Ds[11].…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence implicating the PCP signaling mechanism per se in kidney morphogenesis or in PKD is circumstantial. Numerous Wnts are associated with loss of OCD and/or cysts, but assigning function to PCP vs. other pathways is challenging[8, 13, 27, 28]. Mutations in Inversin, a homolog of Drosophila Diego, cause nephronophthisis type 2[29], however, the association of Inversin with cilia and with both canonical Wnt as well as PCP signaling make interpretation difficult (reviewed in[30]).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic

et al. 2017

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Summary Oriented cell division (OCD) and convergent extension (CE) shape developing renal tubules, and their disruption has been associated with polycystic kidney disease (PKD) genes, the majority of which encode proteins that localize to primary cilia. Core planar cell polarity (PCP) signaling controls OCD and CE in other contexts, leading to the hypothesis that disruption of PCP signaling interferes with CE and/or OCD to produce PKD. Nonetheless, the contribution of PCP to tubulogenesis and cystogenesis is uncertain, and two major questions remain unanswered. Specifically, the inference that mutation of PKD genes interferes with PCP signaling is untested, and the importance of PCP signaling for cystogenic PKD phenotypes has not been examined. We show that during proliferative stages PCP signaling polarizes renal tubules to control OCD. However, we find that contrary to the prevailing model, PKD mutations do not disrupt PCP signaling, but instead act independently and in parallel with PCP signaling to affect OCD. Indeed, PCP signaling that is normally downregulated once development is completed is retained in cystic adult kidneys. Disrupting PCP signaling results in inaccurate control of tubule diameter, a tightly regulated parameter with important physiological ramifications. However, we show that disruption of PCP signaling is not cystogenic. Our results suggest that regulating tubule diameter is a key function of PCP signaling, but that loss of this control does not induce cysts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic

et al. 2017

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“… ) or Wnt11 ( Nagy et al . ) disrupts development of the kidney medullary tubular architecture, resulting in a compromised urine concentrating capacity. Therefore, deficits in Wnt/β‐catenin signalling following hypoxia strongly suggest the existence of an underlying mechanism for perturbed medullary development and function in these offspring.…”

Section: Discussionmentioning

confidence: 99%

Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring

Walton

Singh

Little

et al. 2018

The Journal of Physiology

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Prenatal hypoxia is a common perturbation to arise during pregnancy, and can lead to adverse health outcomes in later life. The long-lasting impact of prenatal hypoxia on postnatal kidney development and maturation of the renal tubules, particularly the collecting duct system, is relatively unknown. In the present study, we used a model of moderate chronic maternal hypoxia throughout late gestation (12% O exposure from embryonic day 14.5 until birth). Histological analyses revealed marked changes in the tubular architecture of male hypoxia-exposed neonates as early as postnatal day 7, with disrupted medullary development and altered expression of Ctnnb1 and Crabp2 (encoding a retinoic acid binding protein). Kidneys of the RARElacZ line offspring exposed to hypoxia showed reduced β-galactosidase activity, indicating reduced retinoic acid-directed transcriptional activation. Wild-type male mice exposed to hypoxia had an early decline in urine concentrating capacity, evident at 4 months of age. At 12 months of age, hypoxia-exposed male mice displayed a compromised response to a water deprivation challenge, which was was correlated with an altered cellular composition of the collecting duct and diminished expression of aquaporin 2. There were no differences in the tubular structures or urine concentrating capacity between the control and hypoxia-exposed female offspring at any age. The findings of the present study suggest that prenatal hypoxia selectively disrupts collecting duct patterning through altered Wnt/β-catenin and retinoic acid signalling and this results in impaired function in male mouse offspring in later life.

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“…The role of Wnt11 in later stage of mammalian kidney organogenesis is established and supported by the anomalies in kidney tubular system and secondary glomerular cysts in Wnt11 −/− null mice, which is consistent with its early involvement in UB branching. 58 These effects presumably act through several downstream genes implicated in kidney development, such as Wnt9b, Six2, Foxd1, Hox10 , and Dvl2 . 58 …”

Section: Wnt Signaling and Kidney Developmentmentioning

confidence: 99%

“…58 These effects presumably act through several downstream genes implicated in kidney development, such as Wnt9b, Six2, Foxd1, Hox10 , and Dvl2 . 58 …”

Section: Wnt Signaling and Kidney Developmentmentioning

confidence: 99%

Wnt Signaling in Kidney Development and Disease

Wang

Zhou

Liu

2018

Progress in Molecular Biology and Translational Science

105

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Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.

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Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Cited by 22 publications

References 48 publications

Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic

Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic

Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring

Wnt Signaling in Kidney Development and Disease

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