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  • 1
    Online Resource
    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
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  • 2
    Online Resource
    Online Resource
    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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  • 3
    Online Resource
    Online Resource
    483-P: Key Biochemical and Histopathological Markers of Diabetic Nephropathy Correlate with Hypertension in the Renin-AAV Uninephrectomized db/db Mouse Model
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Introduction: Diabetic nephropathy (DN) is a long-term complication that occurs in ∼40% of diabetes patients and is a leading cause of end-stage renal disease. In a newly established mouse model of progressive DN, we investigated the effects of hypertension on kidney injury. Methods: Female db/db mice were uninephrectomized (UNx) at 8 weeks of age and injected i.v. with a Renin adeno-associated virus (AAV) construct at different doses to induce hypertension, while a LacZAAV construct was used as negative control. Sham-operated db/+ mice served as healthy controls. Blood pressure and glomerular filtration rate (GFR) was measured at 22 weeks of age, while urine albumin to creatinine ratio (ACR) was measured before termination and kidney tissue sampling 24 weeks of age. Results: GFR measurements indicated hyperfiltration in all AAV-injected UNx db/db mice compared to db/+ mice, while ReninAAV tended to dose-dependently decrease GFR compared to LacZAAV in UNx db/db mice. Urine ACR was worsened by ReninAAV-induced hypertension compared to LacZAAV controls. 3D kidney imaging demonstrated increased glomerular volume in LacZAAV UNx db/db mice compared to db/+ mice with no further effect in ReninAAV groups. Automized AI-based glomerulosclerosis scoring showed ReninAAV dose-dependent increases in glomerulosclerosis compared to LacZAAV controls. RNA sequencing revealed upregulated gene expression markers of kidney fibrogenesis (Col1a1, Col4, Fn1) and tubular injury (Ngal and Kim-1), as well as downregulation of proximal tubular markers (Megalin, Aqp1) in ReninAAV UNx db/db mice compared to LacZAAV controls. Conclusion: ReninAAV-induced hypertension in female UNx db/db mice aggravates albuminuria and glomerulosclerosis paralleled by increased expression of genes associated with tubular injury renal fibrosis, thus confirming that ReninAAV UNx db/db mice is a reliable model of DN with features of late stage human disease. Disclosure M.V. Østergaard: None. I.R. Sørensen: None. A.A. Pedersen: None. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Gubra. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. F.E. Sembach: Employee; Self; Gubra. M.R. Madsen: None. K. Fosgerau: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-483-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    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
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  • 5
    Online Resource
    Online Resource
    Unbiased Stereological Quantification of Key Features of Diabetic Nephropathy
    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 serious long-term complication of diabetes. There is no curative treatment of DN, and the lack of knowledge about mechanisms leading to DN hampers the development of efficient therapies. To facilitate drug development, the ability to quantify key histopathological changes in animal models of human DN is essential. In order to develop a more precise determination of translatable nephrotic changes, we used novel and refined image analyses and stereological quantification of key features of DN in a model approach combining genetic diabetes (db/db mice) with uninephrectomy (UNx). UNx or sham-operation was performed in db/db or db/+ male and female mice (n=8-16 mice per group) and the study was terminated 10 or 16 weeks after surgery. Diabetes development was similar in sham and UNx db/db mice. Compared to sham-operation, UNx increased average kidney weight in db/db females both after 10 (43%) and 16 weeks (48%). Blood urea nitrogen (BUN) was increased in UNx vs. sham-operated animals 4 weeks post-surgery, but not at termination. Notably, kidney fibrosis was increased in UNx and sham db/db vs. sham db/+ females (16 weeks; mg total collagen; 12.7 ± 1.3 and 10.7 ± 1.8, respectively, vs. 5.7 ± 0.8, p & lt;0.05). Urinary albumin was progressively increased in all db/db groups with significantly lower variance in UNx db/db females than sham (F-test, p=0.02), permitting smaller group sizes in pre-clinical studies. Unbiased stereological quantification is ongoing to establish volume of glomeruli and number of podocytes. Glomerular collagen is quantified by double-fluorescence imaging concomitantly detecting podocin and collagen. In conclusion, renal hypertrophy and raised plasma BUN suggest increased pressure on the remaining kidney in UNx mice, leading to fibrosis and decreased kidney function. The thorough quantification of translatable features of DN in the db/db UNx model may provide refinement of this model enabling improved pharmacological testing of compounds targeting DN. Disclosure T.X. Pedersen: Employee; Self; Gubra. T.T. Johansen: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-516-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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