Suppression of Adenosine Deaminase and Xanthine Oxidase Activities by Mineralocorticoid and Glucocorticoid Receptor Blockades Restores Renal Antioxidative Barrier in Oral Contraceptive-Treated Dam.

Emmanuel D. Areola,Eleojo Benjamin,Olayemi J. Olajide,Tolulope E. Adegoke,Matthew A. Obekpa,Oluwatobi E. Elijah,Lawrence A. Olatunji,Peter Sever,Olufunto O. Badmus,Aminu Imam

doi:10.1155/2021/9966372

Abstract

Objective We tested the hypothesis that postpartum combined oral contraceptive (COC) treatment would induce oxidative stress via the adenosine deaminase-xanthine oxidase pathway in the kidney. We also sought to determine whether mineralocorticoid receptor (MR) or glucocorticoid receptor (GR ) blockade would suppress the activities of ADA and xanthine oxidase caused by postpartum COC treatment in the kidney. Methods Twenty-four Wistar dams were randomly assigned to 4 groups (n = 6/group). Dams received vehicle (po), COC (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; po), COC with GR blockade (mifepristone; 80.0 mg/kg; po), and COC with MR blockade (spironolactone; 0.25 mg/kg; po) daily between 3rd and 11th week postpartum. Results Data showed that postpartum COC caused increased plasma creatinine and urea, increased renal triglyceride/high-density lipoprotein ratio, free fatty acid accumulation, alanine aminotransferase, gamma-glutamyltransferase, uric acid, and activities of renal XO and ADA. On the other hand, postpartum COC resulted in decreased plasma albumin, renal glutathione, and Na+-K+-ATPase activity with no effect on lactate production. However, MR or GR blockade ameliorated the alterations induced by postpartum COC treatment. The present results demonstrate that MR or GR blockade ameliorates postpartum COC-induced increased activities of ADA and xanthine oxidase and restores glutathione-dependent antioxidative defense. Conclusion These findings implicate the involvements of GR and MR in renal dysfunctions caused by COC in dams via disrupted glutathione antioxidative barrier.

Highlights

Incidence of chronic kidney disease (CKD) is increasing globally due to complications associated with the epidemic of metabolic disturbances [1]
There was a significant increase in renal triglyceride/high-density lipoprotein (TG/HDL) ratio and free fatty acid (FFA) but reduction in total cholesterol/high-density lipoprotein (TC/HDL) ratio in combined oral contraceptive- (COC-) treated rats compared with control (Figures 2(a)–2(c))
There was reduction in TC/HDL ratio in animals exposed to postpartum COC that received mineralocorticoid receptor (MR) but not glucocorticoid receptor (GR) blocker compared with control

Summary

Introduction

Incidence of chronic kidney disease (CKD) is increasing globally due to complications associated with the epidemic of metabolic disturbances [1]. Several factors may contribute to the progression of CKD including oxidative stress, inflammation, derangements of renal hemodynamics, and excess activation of renin–angiotensin–aldosterone system (RAAS) [2,3]. Aldosterone is a key hormone in mineralocorticoid receptor (MR) activation. Previous animal study reported that aldosterone participates in the progression of kidney disease through hemodynamic. An earlier study has it that glucocorticoids are involved in the development of renal injury through a mineralocorticoid receptordependent mechanism [7]. Several studies have described a correlation between loss of renal function and glucocorticoid receptor (GR) activation by 11β-HSD enzymes [8,9]. Progression of chronic renal failure is related to excess glucocorticoid production [10]

Methods

Results

Conclusion