Sex‐dependent differences in renal angiotensinogen as an early marker of diabetic nephropathy

Abstract

Accepted ArticleThis article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/apha.12441 This article is protected by copyright. All rights reserved. Accepted ArticleThis article is protected by copyright. All rights reserved. Running Title:Renal angiotensinogen in diabetic nephropathy Abstract AIM. The renal renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic nephropathy. The aim of this study was to investigate sex differences in renal renin-angiotensin system (RAS) and the roles of androgens in diabetes-associated renal injury. METHODS.Renal injury and fibrosis was studied in streptozotocin-induced diabetic Accepted ArticleThis article is protected by copyright. All rights reserved.CONCLUSIONS. These data indicate that renal but not hepatic AOGEN or renin is positively associated with diabetic albuminuria and contribute to the sex-dependent differences in renal injury. Androgens may contribute to albuminuria in male independently of the RAS.

RAS and sex differences in diabetic nephropathy

“…Diabetic and hypertensive females also exhibited greater glomerular vascular endothelial growth factor staining and higher levels of inflammation in terms of tubulointerstitial CD68 ϩ cells within the kidney (140). Of note, the onset and duration of diabetes in these studies were clearly different (24,140), which probably determined a different hormonal status at the end of each follow-up. These data suggest that sex-specific susceptibility to develop certain features of DN can vary according to different factors, such as age, diabetes duration, and the presence of hypertension.…”

“…In STZ-induced 6-wk-old Sprague-Dawley rats, 12 wk of T1DM led to significantly higher albuminuria and systolic blood pressure in diabetic males compared with females. In addition, diabetic males, but not females, showed increased renal collagen I and fibronectin mRNA levels compared with controls (24). In contrast, when STZ was administrated to 11-wk-old mRen2.Lewis hypertensive rats, diabetic females exhibited a marked increase in the inflammatory marker C-reactive protein that was not evident in the diabetic males.…”

“…Clinical and experimental studies have also shown sex differences in RAS components in several tissues and in the circulation (33,94,100,140). In addition, chemical and surgical castration modulate the expression of different RAS components such as angiotensinogen (AOGEN), renin, angiotensin-converting enzyme (ACE), and ACE2 (24,57,59).…”

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

“…This was followed by MS2 scan acquisition of the top 12 parent ions with resolution 17,500. The following parameters were enabled: monoisotopic precursor selection, charge state screening, and dynamic exclusion (enabled for 45 s), MS1 target value of 3e 6 and maximum injection time (IT) of 100 ms, MS2 target value of 5e 4 with maximum IT of 50 ms, isolation window of 1.6 Da, normalized collision energy (NCE) of 27, peptide match set to preferred, underfill ratio set to 2% (underfill ratio of 2e 4 ), exclude isotopes set to ON. In addition, charge states of ϩ1, Ͼ4, and unassigned charge states were not subjected to MS2 fragmentation.…”

“…At a clinical level, it is generally accepted that male sex is a risk factor for CKD (3). In addition, sex differences impact the progression of renal disease in animal models of non-diabetic (4) and diabetic nephropathy (5)(6)(7).…”