scholarly journals A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 251
Author(s):  
Hye Sook Min ◽  
Ji Eun Lee ◽  
Jung Yeon Ghee ◽  
Young Sun Kang ◽  
Jin Joo Cha ◽  
...  
Keyword(s):  
Renal Disease ◽  
Structural Changes ◽  
Immunosuppressive Agent ◽  
Term Treatment ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
Long Term Treatment ◽  
Cyclosporine Nephrotoxicity ◽  
Progression Of Renal Disease

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

Abstract 15107: Long-Term Treatment With Sitagliptin Provides Multiple Ultrasonic-Evaluated Antiatherosclerotic Effects Independent of Diabetic Improvement for Type-2 Diabetics

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tatsuaki Murakami ◽  
Sumio Mizuno
Keyword(s):  
Intima Media Thickness ◽  
Term Treatment ◽  
Dipeptidyl Peptidase 4 ◽  
Type 2 Dm ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
Type 2 Diabetics ◽  
Long Term Treatment ◽  
High Resolution Ultrasonography

Introduction: Diabetes mellitus (DM) is thought to be highly involved in complex atherothrombogenic processes, but the long-term antiatherosclerotic therapies in patients with type-2 DM have not been established. Hypothesis: Therefore we assessed hypothesis long-term treatment sitagliptin, a dipeptidyl peptidase-4 inhibitor recently developed antidiabetic agent, chronically inhibits atherosclerotic progression in patients with type-2 DM. Methods: Thirty-two type-2 diabetic patients with stable coronary artery disease were randomized to group-S where they received sitagliptin (50mg/day), or to group-C where they received enhanced antidiabetic therapy without a dipeptidyl peptidase-4 inhibitor for 2 years. We quantified flow-mediated endothelium-dependent dilation of right brachial artery after 5 minutes forearm occlusion (BFMD), and intima-media thickness of brachial artery (BIMT) using high-resolution ultrasonography. We also quantified intima-media thickness of common carotid artery (CIMT) using high-resolution ultrasonography. Changes in BFMD, BIMT, and CIMT were compared between the two study groups. Results: Group-S (n=16) manifested good compliance to the long-term treatment and improvements in diabetic and lipid variables represented by HbA1c and LDL after long-term medication of sitagliptin, while there were no improvements in group-C. BFMD (%) improved after medication in group-S (from 3.9±1.8 to 6.4±2.6, p<0.01) and BIMT (mm) decreased in group-SG (from 0.35±0.10 to 0.32±0.11, p=0.03), while both remained unchanged in group-C (BFMD; from 4.1±2.0 to 4.1±1.9, p=0.88, BIMT; from 0.34±0.13 to 0.35±0.12, p=0.54). CIMT (mm) did not increase in group-S (from 1.10±0.35 to 1.08±0.39, p=0.16) but increased in group-C (from 1.09±0.46mm to 1.16±0.47mm, p<0.01). Changes of BFMD or BIMT in group-S did not correlate to those of HbA1c (BFMD: r=0.17, p=0.79, BIMT: r=0.11, p=0.85). Conclusions: This study suggests that long-term treatment of sitagliptin safely improves arterial function and inhibits progression of wall thickness independent of reversal for diabetic status, which may have beneficial potentials for long-term management of atherosclerosis in type-2 diabetics.

scholarly journals Endothelin research and the discovery of macitentan for the treatment of pulmonary arterial hypertension

2016 ◽  
Vol 311 (4) ◽  
pp. R721-R726 ◽  
Author(s):  
Martine Clozel
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Term Treatment ◽  
Vasopressin Release ◽  
Long Term Treatment ◽  
Pulmonary Arterial ◽  
Kinetics Of

Endothelin receptor antagonists (ERAs) are used for the treatment of pulmonary arterial hypertension (PAH). Macitentan, a dual (ETA+ETB) ERA approved for the long-term treatment of PAH, was discovered through a tailored research program aimed at improving efficacy and safety over the existing ERAs. The goal of improved efficacy was based on the understanding that not only the ETA receptor but also the ETB receptor contributed to the hemodynamic and structural changes induced by endothelin-1 (ET-1) in pathological conditions and on the predefined requirements for optimal tissue penetration and binding kinetics of the antagonist. The goal of improved safety was based on the discovery of the role of ETB receptors in vascular permeability and vasopressin release and on the elucidation of the mechanism by which bosentan (the first approved oral dual ETA/ETB ERA) caused liver enzyme changes. Our intention was to design a molecule that would block ETA and ETB receptors optimally and would not interfere with bile salt elimination. This review takes us through the drug discovery journey that led to the discovery, development, and registration of macitentan.

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