Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Gupta, Deepak Prasad; Hwang, Jae-Won; Cho, Eui-Sic; Kim, Won; Song, Chang Ho; Chai, Ok Hee

doi:10.1159/000464460

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…Expression of Smo-M2 alone during postnatal development using Pkhd1 Cre did not generate cysts (data not shown), consistent with a previous report. 39 Concomitant expression of Smo-M2 and inactivation of Pkd1 in the early postnatal collecting duct did not alter the kidney cystic phenotype compared with Pkd1 deletion alone ( Figure 2, A and B). We also tested whether ligandindependent activation of the Hedgehog pathway could influence polycystic disease in the slower-progressing adult-onset ADPKD model.…”

Section: Activation Of Hedgehog Pathway In Renal Epithelial Cells Doementioning

confidence: 90%

Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Ma¹,

Legué

Tian³

et al. 2019

JASN

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BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

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Section: Activation Of Hedgehog Pathway In Renal Epithelial Cells Doementioning

confidence: 90%

Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Ma¹,

Legué

Tian³

et al. 2019

JASN

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“…Recent research has focused on the Ptch structure (8,11), but it had still not proved that the expression of Ptch (P1 and P2) is abnormal in UPJO. Gupta et al found that the expression of P1 in hydronephrotic mice model was high compared to normal (10). His research was based on arti cial mutant mice, not on real UPJO patients.…”

Section: Discussionmentioning

confidence: 99%

“…Despite various investigations, the Ptch regulation in UPJO children remains unclear, and whether there is variation is yet to be proved (9). The expression of P1 and P2 have been compared in hydronephrotic models and contiguous segments in the same patients' ureters in previous studies, but the same parts of human ureteropelvic junction segments have not been compared (5,10).…”

Section: Introductionmentioning

confidence: 99%

The Expression of Ptch1 and Ptch2 in the Stenotic Tissue of Congenital Ureteropelvic Junction Obstruction in Children

YANG

han

Zhang

et al. 2020

Preprint

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Background: Ptch1 and Ptch2 are expressed in tubular epithelium and stromal cells adjacent to the UPJ. They mediate inhibition of Smoothened, a transmembrane protein expressed on the cell surface. If the pathway is disturbed, UPJOcan occur. This aim study aimed to determine the expression of Ptch1 (P1) and Ptch2 (P2) in stenotic segments in children with congenital ureteropelvic junction obstruction (UPJO) compared with normal control subjects. Methods: Stenotic segments of ureter tissues were obtained from 20 UPJO patients.UPJO caused by other pathogenies, such as vessel and ureteral polyps, were excluded. The control ureter specimens were obtained from 10 patients with Wilm’s tumor, and the tissues were confirmed histologically to be unaffected. Immunofluorescence, western blot and real-time PCR were used to investigate the expression of P1 and P2. Statistical methods were used to find the differences between the two groupsResults: P1 and P2 were identified in the cytoplasm of smooth muscle in two groups through immunohistochemistry. However, there were no statistical differences between the two groups in P1 and P2 with immunohistochemistry (P=0.31 and P=0.3, respectively). There were also no statistical differences with western blot (P=0.75 and P=0.9, respectively) and real-time PCR (P=0.52 and P=0.45, respectively). However, with the immunofluorescence it was found that red-stained P1 were diffused in the controls group, but were mainly located in the intracellular perinuclear compartment of smooth muscle cells in UPJO. Conclusions: The expression of P1 and P2 between the two groups had no statistical significant. P1 were mainly located in the intracellular perinuclear compartment of smooth muscle cells in UPJO. The P1 pathway might be disturbed by the abnormal distribution rather than the quantity, which might be one probable pathogenesis of UPJO.

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“…The germline loss of Smo results in embryonic lethality prior to metanephric kidney development. Smo deletion from the ureteric epithelium does not cause detectable phenotypes (Cain et al, 2009) although expression of constitutively active Smo in the ureteric epithelium leads to renal hypoplasia and hydronephrosis (Gupta et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development

Desai

Agustin

Stuck

et al. 2018

Mechanisms of Development

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Eukaryotic cilia are assembled by intraflagellar transport (IFT) where large protein complexes called IFT particles move ciliary components from the cell body to the cilium. Defects in most IFT particle proteins disrupt ciliary assembly and cause mid gestational lethality in the mouse. IFT25 and IFT27 are unusual components of IFT-B in that they are not required for ciliary assembly and mutant mice survive to term. The mutants die shortly after birth with numerous organ defects including duplex kidneys. Completely duplex kidneys result from defects in ureteric bud formation at the earliest steps of metanephric kidney development. Ureteric bud initiation is a highly regulated process involving reciprocal signaling between the ureteric epithelium and the overlying metanephric mesenchyme with regulation by the peri-Wolffian duct stroma. The finding of duplex kidney in Ift25 and Ift27 mutants suggests functions for these genes in regulation of ureteric bud initiation. Typically the deletion of IFT genes in the kidney causes rapid cyst growth in the early postnatal period. In contrast, the loss of Ift25 results in smaller kidneys, which show only mild tubule dilations that become apparent in adulthood. The smaller kidneys appear to result from reduced branching in the developing metanephric kidney. This work indicates that IFT25 and IFT27 are important players in the early development of the kidney and suggest that duplex kidney is part of the ciliopathy spectrum.

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Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Cited by 6 publications

References 55 publications

Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

The Expression of Ptch1 and Ptch2 in the Stenotic Tissue of Congenital Ureteropelvic Junction Obstruction in Children

Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development

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