title: DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy.
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 highdose 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 µg/24 h vs. 170.8 ± 34.2 µg/24 h; P=0.017), whereas the effects of single treatment with either telmisartan (97.8 ± 26.4 µg/24 h) or linagliptin (120.8 ± 37.7 µg/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.
authors.affiliation: Department of Nephrology, Charité, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus L
authors.initials: ML
authors.lastname: Alter
authors.forename: Ina M
authors.initials: IM
authors.lastname: Ott
authors.forename: Karoline
authors.initials: K
authors.lastname: von Websky
authors.forename: Oleg
authors.initials: O
authors.lastname: Tsuprykov
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Sharkovska
authors.forename: Katharina
authors.initials: K
authors.lastname: Krause-Relle
authors.forename: Jens
authors.initials: J
authors.lastname: Raila
authors.forename: Andrea
authors.initials: A
authors.lastname: Henze
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D000069476:Linagliptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D013311:Streptozocin / Q000009:adverse effects; D000077333:Telmisartan; D016896:Treatment Outcome
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D004791:Enzyme Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D013311:Streptozocin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000077333:Telmisartan