@article{AlterKretschmerVonWebskyetal.2012,
  author    = {Alter, Markus L. and Kretschmer, Axel and Von Websky, Karoline and Tsuprykov, Oleg and Reichetzeder, Christoph and Simon, Alexandra and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {Early urinary and plasma biomarkers for experimental diabetic Nephropathy},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {58},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {7-8},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  doi       = {10.7754/Clin.Lab.2011.111010},
  pages     = {659 -- 671},
  year      = {2012},
  abstract  = {Background: As the prevalence of diabetes rises, its complications such as diabetic nephropathy affect an increaseing number of patients. Consequently, the need for biomarkers in rodent models which reflect the stage and course of diabetic nephropathy is high. This article focuses on Heart-type fatty acid binding protein (H-FABP), osteopontin (OPN), nephrin, and Neutrophil gelatinase-associated lipocalin (NGAL) in urine, and kidney injury molecule (KIM)-1, clusterin, and tissue inhibitior of metalloproteinases (TIMP) 1 in plasma in uni-nephrectomized rats with streptocotozin-induced type 1 diabetes mellitus, a common animal model to explore renal impairment in the setting of diabetes mellitus. Methods: 23 male Wistar rats were uni-nephrectomized and subsequently divided into two study groups. The diabetic group received streptozotocin (STZ) via tail-vein injection, the non-diabetic group received citrate buffer without STZ. Subsequently, blood glucose, body weight, and blood pressure were checked regularly. After 18 weeks, animals were placed in metabolic cages, blood and urine obtained and subsequently organs were harvested after sacrifice. Results: Blood glucose levels were highly increased in diabetic animals throughout the experiment, whereas systolic blood pressure did not differ between the study groups. At study end, classical biomarkers such as urinary albumin and protein and plasma cystatin c were only slightly but not significantly different between groups indicating a very early disease state. In contrast, urinary excretion of H-FABP, OPN, nephrin, and NGAL were highly increased in diabetic animals with a highly significant p-value (p<0.01 each) compared to non-diabetic animals. In plasma, differences were found for calbindin, KIM-1, clusterin, TIMP-1, and OPN. These findings were confirmed by means of the area under the receiver operating characteristic curve (ROC-AUC) analysis. Conclusions: In summary, our study revealed elevated levels of new plasma and urinary biomarkers (urinary osteopontin, urinary nephrin, urinary NGAL, urinary H-FABP, plasma KIM-1, plasma TIMP-1) in uni-nephrectomized diabetic rats, an established rat model of diabetic nephropathy. These biomarkers appeared even before the classical biomarkers of diabetic nephropathy such as albuminuria and urinary protein excretion. The new biomarkers might offer advantage to urinary albumin and plasma cystatin c with respect to early detection.},
  language  = {en}
}
@article{AlterOttvonWebskyetal.2012,
  author    = {Alter, Markus L. and Ott, Ina M. and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Klein, Thomas and Hocher, Berthold},
  title     = {DPP-4 Inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy},
  series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  volume    = {36},
  journal   = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  number    = {1},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1420-4096},
  doi       = {10.1159/000341487},
  pages     = {119 -- 130},
  year      = {2012},
  abstract  = {Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 +/- 2.3 mmHg vs 117.1 +/- 2.2 mmHg; mean +/- SEM; P = 0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 +/- 15.3 mu g/24 h vs 170.8 +/- 34.2 mu g/24 h; P = 0.017), whereas the effects of single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or linagliptin (120.8 +/- 37.7 mu g/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p < 0.01 and p < 0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.},
  language  = {en}
}
@misc{HocherReichetzederAlter2012,
  author    = {Hocher, Berthold and Reichetzeder, Christoph and Alter, Markus L.},
  title     = {Renal and cardiac effects of DPP-4 inhibitors - from preclinical development to clinical research},
  series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  volume    = {36},
  journal   = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  number    = {1},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1420-4096},
  doi       = {10.1159/000339028},
  pages     = {65 -- 84},
  year      = {2012},
  abstract  = {Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined Phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal Phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure.},
  language  = {en}
}
@article{OttAltervonWebskyetal.2012,
  author    = {Ott, Ina M. and Alter, Markus L. and von Websky, Karoline and Kretschmer, Axel and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade},
  series = {PLOS ONE},
  volume    = {7},
  journal   = {PLOS ONE},
  number    = {8},
  publisher = {PUBLIC LIBRARY SCIENCE},
  address   = {SAN FRANCISCO},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0042623},
  pages     = {9},
  year      = {2012},
  abstract  = {The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.},
  language  = {en}
}
@inproceedings{SharkovskaAlterReichetzederetal.2012,
  author    = {Sharkovska, Y. and Alter, Markus L. and Reichetzeder, Christoph and Tsuprykov, Oleg and Klein, T. and Hocher, Berthold},
  title     = {DPP-4 inhibition with linagliptin delays the progression of diabetic nephropathy in db/db mice},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {55},
  booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {5},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  pages     = {S20 -- S20},
  year      = {2012},
  language  = {en}
}