Journal Article

DPP-4 Inhibition on Top of Angiotensin Receptor Blockade Offers a New Therapeutic Approach for Diabetic Nephropathy

Alter, Markus L., Henze, Andrea, Hocher, Berthold, Krause-Relle, Katharina, Tsuprykov, Oleg, Klein, Thomas, Sharkovska, Yuliya, Ott, Ina M., Raila, Jens, von Websky, Karoline

2012

Overview

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.

• Publisher: S. Karger AG
• Subject: Angiotensin Receptor Antagonists - pharmacology / Angiotensin Receptor Antagonists - therapeutic use / Animals / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Benzoates - pharmacology / Benzoates - therapeutic use / Blood Pressure - drug effects / Blood Pressure - physiology / Diabetes Mellitus, Experimental - chemically induced / Diabetes Mellitus, Experimental - complications / Diabetic Nephropathies - drug therapy / Diabetic Nephropathies - etiology / Diabetic Nephropathies - physiopathology / Dipeptidyl Peptidase 4 - drug effects / Dipeptidyl Peptidase 4 - physiology / Disease Models, Animal / Drug Therapy, Combination / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Linagliptin / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Nitric Oxide Synthase Type III - deficiency / Nitric Oxide Synthase Type III - genetics / Nitric Oxide Synthase Type III - physiology / Original Paper / Oxidative Stress - drug effects / Oxidative Stress - physiology / Purines - pharmacology / Purines - therapeutic use / Quinazolines - pharmacology / Quinazolines - therapeutic use / Streptozocin - adverse effects / Treatment Outcome