Abstract
While it has been known since the 1940s that men have greater increases in blood pressure (BP) compared with women, there have been intense efforts more recently to increase awareness that ...women are also at risk for developing hypertension and that cardiovascular diseases (CVDs) are the leading causes of death among both men and women in the United States. With the release of the 2017 Hypertension Clinical Guidelines, 46% of adults in the United States are now classified as hypertensive, and hypertension is the primary modifiable risk factor for the development of CVD. This increase in the prevalence of hypertension is reflected in an increase in prevalence among both men and women across all demographics, although there were greater increases in the prevalence of hypertension among men compared with women. As a result, the well-established gender difference in the prevalence of hypertension is even more pronounced and now extends into the sixth decade of life. The goals of this review are to (i) review the historical clinical trial data and hypertension guidelines from the perspective of both genders and then (ii) review the role of the renin–angiotensin system and T-cell activation in contributing to sex differences in BP control.
SUMMARY
The prevalence of diabetes has dramatically increased worldwide due to the vast increase in the obesity rate. Diabetic nephropathy is one of the major complications of type 1 and type 2 ...diabetes and it is currently the leading cause of end‐stage renal disease. Hyperglycemia is the driving force for the development of diabetic nephropathy. It is well known that hyperglycemia increases the production of free radicals resulting in oxidative stress. While increases in oxidative stress have been shown to contribute to the development and progression of diabetic nephropathy, the mechanisms by which this occurs are still being investigated. Historically, diabetes was not thought to be an immune disease; however, there is increasing evidence supporting a role for inflammation in type 1 and type 2 diabetes. Inflammatory cells, cytokines, and profibrotic growth factors including transforming growth factor‐β (TGF‐β), monocyte chemoattractant protein‐1 (MCP‐1), connective tissue growth factor (CTGF), tumor necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), interleukin‐18 (IL‐18), and cell adhesion molecules (CAMs) have all been implicated in the pathogenesis of diabetic nephropathy via increased vascular inflammation and fibrosis. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species are a primary candidate. Thus, targeting oxidative stress‐inflammatory cytokine signaling could improve therapeutic options for diabetic nephropathy. The current review will focus on understanding the relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy to help elucidate the question of which comes first in the progression of diabetic nephropathy, oxidative stress, or inflammation.
Although numerous clinical and experimental studies have clearly identified a sexual dimorphism in blood pressure control, the mechanism(s) underlying gender differences in blood pressure remain ...unclear. Over the past two decades, numerous laboratories have utilized the spontaneously hypertensive rats (SHR) as an experimental model of essential hypertension to increase our understanding of the mechanisms regulating blood pressure in males and females. Previous work by our group and others have implicated that differential regulation of adrenergic receptors, the renin-angiotensin system, oxidative stress, nitric oxide bioavailability and immune cells contribute to sex differences in blood pressure control in SHR. The purpose of this review is to summarize previous findings to date regarding the mechanisms of blood pressure control in male versus female SHR.
Vascular Biology Center and Department of Pharmacology, Medical College of Georgia, Augusta, Georgia
The purpose of this review is to examine sex differences in response to stimulation and inhibition ...of the renin-angiotensin system (RAS). The RAS plays a prominent role in the development of chronic renal disease, and there are known sex differences not only in the expression level of components of the RAS but also in how males and females respond to perturbations of the RAS. In men, renal injury increases in parallel with increased activation of the RAS, while in women, increases in ANG II do not necessarily translate into increases in renal injury. Moreover, both epidemiological and experimental studies have noted sex differences in the therapeutic benefits following angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment. Despite these differences, RAS inhibitors are the most commonly prescribed drugs for the treatment of chronic renal disease, irrespective of sex. This review will examine how males and females respond to stimulation and inhibition of the RAS, with a focus on renal disease.
transforming growth factor-β; nuclear factor- B; janus kinase/signal transducers and activators of transcription; angiotensin-converting enzyme inhibitors; angiotensin receptor blocker
Address for reprint requests and other correspondence: J. C. Sullivan, Medical College of Georgia, Vascular Biology Center, 1459 Laney Walker Blvd., Augusta, GA 30912 (e-mail: jsullivan{at}mail.mcg.edu )
Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in ...renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females.
13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography-mass spectrometry (LC/MS).
Male SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR.
Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.
Acute kidney injury (AKI) due to ischemia‐reperfusion (IR) is a serious and frequent complication in hospital setting with high mortality rates. The mechanisms mediating renal IR injury leading to ...increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood. Glutathione peroxidase 4 (GPx4) is a negative regulator of 12/15 lipoxygenase (12/15 LOX) and any alteration in 12/15 LOX and GPx4 activity has been reported to contribute to the progression of kidney diseases. The goal of the current study was to test the hypothesis that an imbalance of 12/15 LOX/GPx4 activity in males leads to impaired recovery following IR compared to females. 13‐week‐old male and female SHR were subjected to sham or 30‐minute warm bilateral IR (n=6/group). Additional male SHR were randomized to receive vehicle or the GPx4 activity mimic ebselen (10 mg/kg i.p.; n=5/group) 1 hr prior to sham/IR, 1 day and 3‐day post IR. Blood and urine were collected from all rats 1 and 7 days after IR; kidneys were harvested 7 days post‐IR for biochemical, histological, and Western blot analysis. IR increased plasma creatinine (Pcr) and blood urea nitrogen (BUN) in both male and female SHR compared to respective sham controls at 24 hrs (PIR =0.0001; Psex*IR=0.2). At 7 days post‐IR, Pcr and BUN remained elevated in male SHR but returned to baseline levels in females (Pcr: PIR =0.03; Psex*IR=0.04; BUN: PIR <0.05; Psex*IR=0.05). Histological examination of kidneys 7 days post‐IR showed greater tubular damage (PIR=0.0003, Psex*IR=0.0019) and renal cell death (PIR=0.001; Psex*IR=0.001) in male vs. female SHR. Delayed recovery of renal function in male SHR was associated with activation of renal 12/15 LOX (PIR<0.05; Psex*IR=0.008), reduced renal GPx4 protein expression (PIR=0.05; Psex*IR<0.001), activity (PIR=0.01; Psex*IR=0.0016), and intracellular glutathione (GSH; PIR=0.01; Psex*IR=0.003), and increased lipid peroxidation (PIR=0.008; Psex*IR=0.018) compared to females. Pre‐treatment of male SHR with ebselen significantly reduced 12/15 LOX induced lipid peroxidation (PIR*TxT =0.02), prevented IR‐induced renal cell death (PIR*TxT=0.04) and tubular damage (PIR*TxT=0.02) and improved renal function (Pcr: PIR*TxT =0.027; BUN: PIR*TxT =0.022) compared to vehicle‐treated IR males 7 days post‐IR. In conclusion, our data demonstrate that increased GPx4 activity enhanced renal recovery post‐IR via inhibiting 12/15 LOX induced oxidative renal cell death in male SHR.
Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator ...6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.
PDF
