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  • 1
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    Online Resource
    Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-09-30)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-09-30)
    Abstract: Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-73046-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 2
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    Online Resource
    Novel Rat Models of Diabetic Nephropathy Displaying Pronounced Tubular Fibrosis and Glomerular Alterations
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Diabetic nephropathy (DN) is a long-term complication of diabetes characterized by proteinuria and loss of kidney function. Up to one third of patients with diabetes develop DN, and no new therapies targeting DN have been introduced for more than a decade. The lack of treatment options may, in part, be caused by the scarcity of translatable rodent models. We have established a surgically induced rat model of non-insulin dependent type 1-like diabetes (90% pancreatectomy, Px), displaying a stable blood glucose of & gt;20 mmol/L. In addition, both Px and uninephrectomy (UNx) was performed simultaneously to potentially increase progression of renal pathological changes. Kidneys in the Px diabetic rat model displayed hypertrophy of glomeruli, cortex, and medulla 11 weeks post-surgery. Renal fibrosis was significantly increased in Px rats vs. nondiabetic control animals, as determined by quantitative histology following picro-sirius red staining of collagen (total kidney collagen, Px vs. controls; 127 ± 8 mg vs. 39 ± 5 mg, p & lt;0.001). Plasma urea was increased in Px rats compared to nondiabetic animals (8.3 ± 0.6 vs. 5.5 ± 0.3 mmol/L, p & lt;0.01). Finally, gene expression of the kidney injury markers NGAL and KIM1 as well as gene expression of pro-fibrotic macrophage markers (mannose receptor, MGL1, and CD163) was increased in Px rat kidneys. Px-UNx rats developed a diabetic phenotype similar to that observed in Px rats. In contrast, a highly increased kidney weight was detected with the more advanced surgical approach. Detailed histological analyses will establish whether glomerular and tubular pathology is exacerbated to a comparable extent. In conclusion, our data suggest that the Px model develops profound renal hypertrophy and fibrosis, and that renal hypertrophy is exacerbated in the Px-UNx model. Thus, Px alone and Px-UNx in rats may represent novel, strong alternatives to streptozotocin-induced diabetes and genetic models for the study of DN drug candidates. Disclosure T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. T.T. Johansen: None. M.V. Oestergaard: None. P.J. Pedersen: None. N.E. Zois: Employee; Self; Gubra. T.X. Pedersen: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Fosgerau: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-502-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 3
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    ZGN-1061, a Novel MetAP2 Inhibitor, and Liraglutide Combine to Improve Glycemic Control and Reduce Body Weight in a Rat Model of Diet-Induced Obesity
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in T2D. This study investigated 5 weeks (weeks) of once-daily SC treatment with a submaximal 0.3 mg/kg dose of 1061, a maximal 0.4 mg/kg dose of liraglutide (lira), 1061+lira, or vehicle (N=10/group) on body weight (BW), food intake/preference, and glycemic control in the Gubra diet-induced obese (DIO) rat model (ad libitum fed chow and highly palatable high-fat, high-sugar [HFHS] diet). Fasting (4 hour) blood glucose (FBG) was collected weekly and a semifasted (16 hour access to 50% of daily energy requirement) OGTT was performed at week 4. At week 5 (day 33), BW changed by +1.7% with vehicle vs. -6.0% with 1061, -9.1% with lira, and -16.9% with 1061+lira (all p & lt;0.001). BW loss occurred earlier with lira (day 1) than 1061 (day 5). Starting at day 6, intake of the HFHS diet was modestly reduced (15-30%) with 1061 vs. vehicle. In contrast, lira and 1061+lira induced rapid and sustained 40-50% and 50-80% reductions in intake of the HFHS diet, respectively, over the first 8-9 days. Cumulative (day 0-35) HFHS diet intake was reduced vs. vehicle by 1061 (13.4%, p=0.07), lira (17.8%, p & lt;0.01), and 1061+lira (38.2%, p & lt;0.001). Cumulative chow intake was increased by 1061 and 1061+lira but not lira alone. There was a modest reduction in FBG (mean week 1-5) with 1061 vs. vehicle (p=0.08), a significant reduction with lira, and 1061+lira produced the largest reduction (both p & lt;0.001) that was significantly lower than either agent alone (both p & lt;0.01). In the OGTT, 1061 reduced the glucose AUC vs. vehicle by 37% (p=0.07), lira by 60% (p & lt;0.001), and 1061+lira by 80% (p & lt;0.001), achieving an AUC that was no different from lean rats. In this DIO rat model, 1061 and lira had complementary effects on reducing BW and normalizing glycemic control. Combination treatment with 1061 and liraglutide may yield greater weight loss and glycemic control than either agent alone in patients with T2D. Disclosure B.F. Burkey: Employee; Self; Zafgen. P.J. Pedersen: None. T.X. Pedersen: Employee; Self; Gubra. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-108-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 4
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    Novel "Dual Hit" Rat Model of Diabetic Cardiomyopathy
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: The pathogenesis of diabetic cardiomyopathy (DC) is poorly understood and new drugs targeting the myocardium are absent. This may be ascribed to the failure of available pre-clinical models to recapitulate essential clinical features of DC and heart failure. We hypothesized that the combination of experimental diabetes and pharmacologically induced cardiac stress might provide a novel rat model displaying a distinct profile of DC. Non-insulin dependent type 1 like diabetes mellitus was induced by partial (90%) pancreatectomy (Px). Pronounced hyperglycemia was established within two weeks (blood glucose levels of 23.3 ± 3.7 mM). Five weeks post Px or sham surgery, vehicle or the sympathomimetic agent, isoproterenol (Iso, 1 mg/kg, SC) was administered for 10 days. Ten weeks after surgery, the heart was isolated for detailed histological and molecular characterization. The relative weight of the left ventricle (LV) was significantly increased in Px-Iso rats compared to sham-vehicle treated control rats (0.22 ± 0.03 vs. 0.25 ± 0.02 mg/g BW, p & lt;0.05), indicating Px-Iso-induced cardiac hypertrophy. Compared to sham-vehicle rats, cardiac muscle fibers of Px-vehicle rats had attenuated respiratory function and increased reliance upon oxidation of fatty acid substrates, measured by high-resolution respirometry. Interestingly, this aggravation was reversed in Px-Iso rats. Moreover, Iso induced cardiac fibrosis demonstrated by quantitative histology (area fraction; Px-vehicle vs. Px-Iso: 3.1 ± 0.2% vs. 6.3 ± 0.5%; Sham-vehicle vs. Sham-Iso: 3.7 ± 0.4% vs. 7.6 ± 0.5%, p & lt;0.001). Echo- and electrocardiography as well as transcriptome analyses were applied to further assess LV remodeling and cardiac function. In conclusion, the Px-Iso rat model may provide a state-of-the-art model of DC displaying key features of the clinical condition. Hereby, this model may be useful in the evaluation of cardiovascular effects of novel compounds in the pre-clinical phase of drug development. Disclosure L. Thisted: Employee; Self; Gubra. R.T. Lindsay: None. K. Fosgerau: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. M.B. Thomsen: None. T. Jespersen: None. A.J. Murray: None. P.J. Pedersen: None. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. T.X. Pedersen: Employee; Self; Gubra. N.E. Zois: Employee; Self; Gubra.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-466-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 5
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    Online Resource
    ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma
    Wiley ; 2006
    In:  International Journal of Cancer Vol. 118, No. 5 ( 2006-03-01), p. 1241-1247
    Details
    In: International Journal of Cancer, Wiley, Vol. 118, No. 5 ( 2006-03-01), p. 1241-1247
    Type of Medium: Online Resource
    ISSN: 0020-7136
    URL: Article
    DOI: 10.1002/ijc.21476
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2006
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 6
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    Lipoprotein(a) accelerates atherosclerosis in uremic mice
    Elsevier BV ; 2010
    In:  Journal of Lipid Research Vol. 51, No. 10 ( 2010-10), p. 2967-2975
    Details
    In: Journal of Lipid Research, Elsevier BV, Vol. 51, No. 10 ( 2010-10), p. 2967-2975
    Type of Medium: Online Resource
    ISSN: 0022-2275
    URL: Article
    DOI: 10.1194/jlr.M006742
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1466675-3
    SSG: 12
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  • 7
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    The pro-inflammatory effect of uraemia overrules the anti-atherogenic potential of immunization with oxidized LDL in apoE−/− mice
    Oxford University Press (OUP) ; 2010
    In:  Nephrology Dialysis Transplantation Vol. 25, No. 8 ( 2010-8), p. 2486-2491
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 25, No. 8 ( 2010-8), p. 2486-2491
    Type of Medium: Online Resource
    ISSN: 1460-2385 , 0931-0509
    URL: Article
    DOI: 10.1093/ndt/gfq059
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2010
    detail.hit.zdb_id: 1465709-0
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  • 8
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    ApoB and apoM – New aspects of lipoprotein biology in uremia-induced atherosclerosis
    Elsevier BV ; 2017
    In:  European Journal of Pharmacology Vol. 816 ( 2017-12), p. 154-160
    Details
    In: European Journal of Pharmacology, Elsevier BV, Vol. 816 ( 2017-12), p. 154-160
    Type of Medium: Online Resource
    ISSN: 0014-2999
    URL: Article
    DOI: 10.1016/j.ejphar.2017.03.053
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1483526-5
    SSG: 15,3
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  • 9
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    Effect of treatment with human apolipoprotein A-I on atherosclerosis in uremic apolipoprotein-E deficient mice
    Elsevier BV ; 2009
    In:  Atherosclerosis Vol. 202, No. 2 ( 2009-2), p. 372-381
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 202, No. 2 ( 2009-2), p. 372-381
    Type of Medium: Online Resource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2008.04.041
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2009
    detail.hit.zdb_id: 1499887-7
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  • 10
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    494-P: Whole-Kidney 3D Imaging and Image Analysis Enables Detailed Quantification of Diabetic Nephropathy Features in the Uninephrectomized db/db Mouse Model
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Diabetic nephropathy (DN) is a serious complication of diabetes and the leading cause of end-stage renal disease. To reproducibly test novel therapies, there is a need for precise quantification of DN pathology in rodent models. We compared the accelerated development of DN in male and female uninephrectomized db/db mice using advanced imaging techniques. Unilateral nephrectomy (UNx) was performed in 7-8 weeks old male and female db/db mice. Sham-operated db/+ mice served as controls. Kidneys were preserved for histology and stereology. In a separate study, UNx was performed in 18 weeks old male db/db mice. These mice and control db/+ mice were injected with lectin-594 prior to termination to visualize glomerular morphology by 3D light sheet microscopy. All mice were terminated at 24 weeks of age. Male and female db/db UNx mice showed comparable increases in albuminuria. Total glomerular volume was markedly higher in male and female db/db UNx mice compared to db/+ controls (mean males; 4.42 vs. 2.71 mm3; p & lt;0.001; females; 5.04 vs. 2.69 mm3; p & lt;0.001). Tubulointerstitial collagen III immuno-staining was significantly increased only in female db/db UNx mice compared to db/+ mice. In contrast, total glomerular collagen IV levels were increased in male db/db UNx mice compared to db/+ controls (mean 1.30 vs. 0.80 mm3; p & lt;0.01), and female db/db UNx mice displayed increased glomerular collagen IV compared to male db/db UNx mice (mean 1.80 vs. 1.30 mm3; p & lt;0.05). 3D imaging at 24 weeks following UNx at 18 weeks of age confirmed expansion in glomerular volume (median db/+ 96.000 vs. db/db 145.000 µm3). Moreover, a marked increase was seen in cortical lectin-594 staining, indicating glomerular leakage in db/db UNx mice. In conclusion, male and female db/db UNx mice displayed comparable features of DN and both constitute valid models for DN. The use of whole-kidney 3D imaging provides a novel avenue for assessment of individual glomerular volume and permeability. Disclosure L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. F.E. Sembach: Consultant; Self; Novo Nordisk A/S. Employee; Self; Gubra. U. Roostalu: Employee; Self; Gubra. T. Johansen: Employee; Self; Gubra. J.L. Skytte: Employee; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Gubra. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. K. Fosgerau: Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. J. Hecksher-Sørensen: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. T.X. Pedersen: Employee; Self; Gubra.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-494-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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