“Effect of Lisinopril and Verapamil on Angiopoietin-2 and Endostatin in Patients with Diabetic Nephropathy”

Abstract

Diabetic nephropathy (DN), a major microvascular complication of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), is an important cause of end stage renal disease (ESRD) in the developed countries. DN is accompanied by persistent albumin urinary excretion or microalbuminuria, which is defined when the albumin/creatinine ratio is 30-299 mg/g in an isolated urine sample in 2 different occasions. Angiogenesis is a multistep process implicated in the pathophysiology and progression of DN. The use of angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have an important role in DN. Angiopioietin-2 (Ang-2) & Endostatin (EST) are mainly used as an angiogenesis biomarker. Dysregulation of the renin–angiotensin-aldosterone system (RAAS) has a critical role in the pathogenesis of chronic kidney disease (CKD). There is an increase of glomerular capillary pressure due to continuous stimulation from the RAAS, which enhances oxidative stress and stimulates pro-inflammatory pathways. These mechanisms promote glomerular hypertrophy, which is present at an early stage of DN and is the beginning of profibrotic cascade. Moreover, calcium antagonists have been demonstrated to inhibit Ang-2 as a vasoconstrictive, hypertrophic and hyperplastic agent via blocking the calcium-dependent mechanism In view of these data, we study the effect of lisinopril alone or in combination with verapamil on DN in T2DM patients with hypertension (HTN) and urinary albumin/creatinine ratio (UACR) of 30-300 mg/g through their effect on angiogenic factors Ang-2 and EST in order to provide a new approach in determining antihypertensive drug options that improve or delay the progression of DN This study was carried out on 150 subjects who were divided into group 1 of 30 healthy control and 120 T2DM patients were screened for eligibility who divided into group 2 of 60 diabetic hypertensive patient without DN and group 3 of 60 diabetic hypertensive patient with DN. 40 patients were enrolled as group 3 (20 males and 20 females) attending Diabetes and Endocrinology Clinic, El Demerdash Hospital, Ain Shams University, Cairo, Egypt. All patients were age- and sex-matched with the healthy controls. The mean age of patients was 50± 4.6 years (range, 45-65 years) while that of controls was 47.64 ± 3.71 (range, 45-65 years). All participants provided an informed consent before their enrollment. The study was approved by the Human Ethical Review Committee, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Each of the eligible patient having T2DM with HTN and (UACR) (30-300 mg/g) was randomly assigned by simple randomization to either Group 3a or Group 3b. Group 3a: consists of 20 patients who received oral lisinopril tablets once daily for 3 months. Group 3b: consists of 20 patients who received oral lisinopril tablets and oral verapamil tablets once daily for 3 months.