Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt–Hogg–Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.

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Role of thin descending limb urea transport in renal urea handling and the urine concentrating mechanism

AJP Renal Physiology ◽

10.1152/ajprenal.00404.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. F1251-F1259 ◽

Cited By ~ 35

Author(s):

Tianluo Lei ◽

Lei Zhou ◽

Anita T. Layton ◽

Hong Zhou ◽

Xuejian Zhao ◽

...

Keyword(s):

Knockout Mice ◽

Gene Knockout ◽

Embryonic Stem ◽

Urine Osmolality ◽

Peripheral Circulation ◽

Solute Concentration ◽

Urine Concentration ◽

Wild Type ◽

Double Knockout ◽

Knockout Mouse Model

Urea transporters UT-A2 and UT-B are expressed in epithelia of thin descending limb of Henle's loop and in descending vasa recta, respectively. To study their role and possible interaction in the context of the urine concentration mechanism, a UT-A2 and UT-B double knockout (UT-A2/B knockout) mouse model was generated by targeted deletion of the UT-A2 promoter in embryonic stem cells with UT-B gene knockout. The UT-A2/B knockout mice lacked detectable UT-A2 and UT-B transcripts and proteins and showed normal survival and growth. Daily urine output was significantly higher in UT-A2/B knockout mice than that in wild-type mice and lower than that in UT-B knockout mice. Urine osmolality in UT-A2/B knockout mice was intermediate between that in UT-B knockout and wild-type mice. The changes in urine osmolality and flow rate, plasma and urine urea concentration, as well as non-urea solute concentration after an acute urea load or chronic changes in protein intake suggested that UT-A2 plays a role in the progressive accumulation of urea in the inner medulla. These results suggest that in wild-type mice UT-A2 facilitates urea absorption by urea efflux from the thin descending limb of short loops of Henle. Moreover, UT-A2 deletion in UT-B knockout mice partially remedies the urine concentrating defect caused by UT-B deletion, by reducing urea loss from the descending limbs to the peripheral circulation; instead, urea is returned to the inner medulla through the loops of Henle and the collecting ducts.

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IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice

Cells ◽

10.3390/cells9091949 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1949

Author(s):

Luisa Hahn ◽

Nora Helmrich ◽

Diran Herebian ◽

Ertan Mayatepek ◽

Uta Drebber ◽

...

Keyword(s):

Bile Acids ◽

Knockout Mice ◽

Therapeutic Target ◽

Intestinal Microbiome ◽

Short Term ◽

Double Knockout ◽

Potential Therapeutic Target ◽

Knockout Mouse Model ◽

Th2 Cytokine ◽

Chronic Intrahepatic Cholestasis

The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4−/−). Lack of IL-13 protected Abcb4−/− mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4−/−/IL-13−/− double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4−/−IL-13−/− mice showed significantly reduced hepatic fibrosis. Abcb4−/− mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.

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Abstract P183: Cardiac Deletion of CaMKII Delta and Gamma Protects Against Heart Failure Despite Activation of Calcineurin Signaling

Circulation Research ◽

10.1161/res.109.suppl_1.ap183 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Michael M Kreusser ◽

Lorenz H Lehmann ◽

Stanislav Keranov ◽

Josef-Hermann Gröne ◽

Hugo A Katus ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Knockout Mice ◽

Drug Targets ◽

Cardiac Fibrosis ◽

Phosphorylation Site ◽

Double Knockout ◽

Knockout Mouse Model ◽

Single Knockout ◽

Calcineurin Signaling

CaMKII delta and gamma are the major CaMKII genes expressed in the heart, and both are up-regulated in response to pressure overload. Recently, we have demonstrated that CaMKII delta single knockout mice are protected against cardiac hypertrophy and remodeling. However, the role of CaMKII gamma and potential redundant functions of CaMKII delta and gamma are still elusive. The aim of the present study was to evaluate the function of CaMKII delta and gamma by a cardiomyocyte-specific double knockout mouse model(delta/gamma-CKO). Strikingly, whereas delta and gamma single knockout mice displayed only slightly reduced levels of cardiac phospholamban (PLN) phosphorylation at the CaMKII phosphorylation site threonin 17, in delta/gamma-CKO mice there was almost no residual PLN-threonin-17 phosphorylation detectable. Surprisingly and in contrast to delta and gamma single knockout mice, delta/gamma-CKO mice did develop cardiac hypertrophy after transverse aortic constriction (TAC). Despite cardiac hypertrophy we observed markedly reduced cardiac fibrosis and apoptosis. Microarray analysis revealed a distinct different gene expression profile pointing to an activation of calcineurin in delta/gamma-CKO mice after TAC. Phosphorylation of calcineurin at serine 197, which leads to an inactivation of its enzymatic activity, was almost abolished in delta/gamma-CKO mice. To test the therapeutical implications of a complete myocardial CaMKII knockout, an tamoxifen-inducible knockout system was established. Knockout of CaMKII delta and gamma was induced by administration of tamoxifen three weeks after TAC surgery. Whereas control mice did develop overt heart failure and cardiac remodeling 16 weeks after TAC, delta/gamma-iCKO mice recovered from cardiac dysfunction. Taken together, our mouse genetic studies demonstrate that CaMKII delta and gamma are promising drug targets to restore cardiac function after pathological stress. These data also unmask a cross talk of CaMKII to endogenous calcineurin signaling, which results in adaptive cardiac hypertrophy and not pathological remodeling.

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Correlation of Vasa Vasorum Neovascularization, Inflammation and Plaque Progression in Aortas of ApoE-/-/LDL-/- Double Knockout Mice by Micro-CT

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/s-2006-940982 ◽

2006 ◽

Vol 178 (S 1) ◽

Author(s):

AC Langheinrich ◽

A Michniewicz ◽

DG Sedding ◽

G Walker ◽

PE Beighley ◽

...

Keyword(s):

Knockout Mice ◽

Vasa Vasorum ◽

Plaque Progression ◽

Micro Ct ◽

Double Knockout

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3-Deazaadenosine Inhibits Vasa Vasorum Neovascularization in Aortas of ApoE-/-/LDL-/- Double Knockout Mice

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/s-2008-1073684 ◽

2008 ◽

Vol 180 (S 1) ◽

Author(s):

AC Langheinrich ◽

D Sedding ◽

M Kampschulte ◽

J Wilhelm ◽

W Haberbosch ◽

...

Keyword(s):

Knockout Mice ◽

Vasa Vasorum ◽

Double Knockout

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Transgenic expression of human INS gene in Ins1/Ins2 double knockout mice leads to insulin underproduction and diabetes in some male mice

Frontiers in Bioscience ◽

10.2741/2171 ◽

2007 ◽

Vol 12 (1) ◽

pp. 1586 ◽

Cited By ~ 4

Author(s):

Melis Karaca

Keyword(s):

Knockout Mice ◽

Male Mice ◽

Double Knockout ◽

Transgenic Expression

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Faculty Opinions recommendation of Role of Atg5-dependent cell death in the embryonic development of Bax/Bak double-knockout mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727681479.793532876 ◽

2017 ◽

Author(s):

Sharad Kumar ◽

Donna Denton

Keyword(s):

Cell Death ◽

Embryonic Development ◽

Knockout Mice ◽

Double Knockout ◽

Dependent Cell

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Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

AJP Renal Physiology ◽

10.1152/ajprenal.00518.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. F188-F193 ◽

Cited By ~ 145

Author(s):

Timo Rieg ◽

Takahiro Masuda ◽

Maria Gerasimova ◽

Eric Mayoux ◽

Kenneth Platt ◽

...

Keyword(s):

Knockout Mice ◽

Plasma Concentrations ◽

Sglt2 Inhibitor ◽

Double Knockout ◽

Glucose Reabsorption ◽

Urinary Glucose ◽

Sglt2 Inhibition ◽

Renal Glucose Reabsorption ◽

Glucose Excretion ◽

Free Plasma

In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted.

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