Interleukin 17A: Key Player in the Pathogenesis of Hypertension and a Potential Therapeutic Target.

PURPOSE OF REVIEW: To summarize key advances in our understanding of the role of interleukin 17A (IL-17A) in the pathogenesis of hypertension and highlight important areas for future research and clinical translation. RECENT FINDINGS: While T helper 17 (Th17) cells are major producers of IL-17A, there are several additional innate and adaptive immune cell sources including gamma-delta T cells, innate lymphoid cells, and natural killer cells. IL-17A promotes an increase in blood pressure through multiple mechanisms including inhibiting endothelial nitric oxide production, increasing reactive oxygen species formation, promoting vascular fibrosis, and enhancing renal sodium retention and glomerular injury. IL-17A production from Th17 cells is increased by high salt conditions in vitro and in vivo. There is also emerging data linking salt, the gut microbiome, and intestinal T cell IL-17A production. Novel therapeutics targeting IL-17A signaling are approved for the treatment of autoimmune diseases and show promise in both animal models of hypertension and human studies. Hypertensive stimuli enhance IL-17A production. IL-17A is a key mediator of renal and vascular dysfunction in hypertensive mouse models and correlates with hypertension in humans. Large randomized clinical trials are needed to determine whether targeting IL-17A might be an effective adjunct treatment for hypertension and its associated end-organ dysfunction.

Low Birth Weight, Blood Pressure and Renal Susceptibility.

PURPOSE OF THE REVIEW: The purpose of this review is to highlight the clinical significance of increased renal risk that has its origins in fetal life. This review will also discuss the critical need to identify therapeutic interventions for use in a pregnancy complicated by placental dysfunction and intrauterine growth restriction that can mitigate the developmental origins of kidney disease without inflicting additional harm on the developing fetus. RECENT FINDINGS: A reduction in nephron number is a contributory factor in the pathogenesis of hypertension and kidney disease in low birth weight individuals. Reduced nephron number may heighten susceptibility to a secondary renal insult, and recent studies suggest that perinatal history including birth weight should be considered in the assessment of renal risk in kidney donors. This review highlights current findings related to placental dysfunction, intrauterine growth restriction, increased risk for renal injury and disease, and potential therapeutic interventions.

Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease.

PURPOSE OF THE REVIEW: It is well-established that the age-related increase in blood pressure is augmented after menopause. Yet, the prevalence of hypertension is enhanced in low birth weight women relative to normal birth weight counterparts by 60 years of age suggesting that adverse influences during fetal life heighten cardiovascular risk in later life. RECENT FINDINGS: A changing hormonal milieu may contribute to increased cardiovascular risk that occurs after the menopausal transition. Low birth weight is associated with early age at menopause. A recent study indicates that a shift towards testosterone excess following early reproductive senescence may contribute to the etiology of age-dependent increases in blood pressure in a rodent model of low birth weight. This review will highlight current findings related to postmenopausal hypertension and discuss potential mechanisms that may contribute to the enhanced cardiovascular risk that develops with age in low birth weight women.

Class switching and high-affinity immunoglobulin G production by B cells is dispensable for the development of hypertension in mice.

AIMS: Elevated serum immunoglobulins have been associated with experimental and human hypertension for decades but whether immunoglobulins and B cells play a causal role in hypertension pathology is unclear. In this study, we sought to determine the role of B cells and high-affinity class-switched immunoglobulins on hypertension and hypertensive end-organ damage to determine if they might represent viable therapeutic targets for this disease. METHODS AND RESULTS: We purified serum immunoglobulin G (IgG) from mice exposed to vehicle or angiotensin (Ang) II to induce hypertension and adoptively transferred these to wild type (WT) recipient mice receiving a subpressor dose of Ang II. We found that transfer of IgG from hypertensive animals does not affect blood pressure, endothelial function, renal inflammation, albuminuria, or T cell-derived cytokine production compared with transfer of IgG from vehicle infused animals. As an alternative approach to investigate the role of high-affinity, class-switched immunoglobulins, we studied mice with genetic deletion of activation-induced deaminase (Aicda-/-). These mice have elevated levels of IgM but virtual absence of class-switched immunoglobulins such as IgG subclasses and IgA. Neither male nor female Aicda-/- mice were protected from Ang II-induced hypertension and renal/vascular damage. To determine if IgM or non-immunoglobulin-dependent innate functions of B cells play a role in hypertension, we studied mice with severe global B-cell deficiency due to deletion of the membrane exon of the IgM heavy chain (µMT-/-). µMT-/- mice were also not protected from hypertension or end-organ damage induced by Ang II infusion or deoxycorticosterone acetate-salt treatment. CONCLUSIONS: These results suggest that B cells and serum immunoglobulins do not play a causal role in hypertension pathology.

Chronic Estrogen Supplementation Prevents the Increase in Blood Pressure in Female Intrauterine Growth-Restricted Offspring at 12 Months of Age.

Low birth weight is associated with a greater prevalence of hypertension and an earlier age at menopause in women in later life. Yet, the association between birth weight and blood pressure (BP) in women as they age is not well defined. In a rodent model of low birth weight induced by placental insufficiency, intrauterine growth restriction programs a significant increase in BP by 12 months of age in female growth-restricted offspring that is associated with early reproductive senescence, increased testosterone, and a shift in the hormonal milieu. Thus, this study tested the hypothesis that increased BP in female growth-restricted offspring is abolished by chronic estradiol supplementation. Placebo or 17ß-estradiol valerate mini pellets (1.5 mg for 60-day release) were administered at 12 months of age for 6 weeks. BP, measured in conscious catheterized rats, was significantly increased in placebo-treated growth-restricted relative to placebo-treated control. However, BP was not elevated in estradiol-treated growth-restricted relative to placebo-treated growth-restricted. Estradiol mediates its effects on BP via its receptors and the renin-angiotensin system. BP was decreased in growth-restricted offspring treated with a G-protein coupled receptor agonist, G1 (400 mg/kg for 2 weeks). Renal AT1aR (angiotensin type 1a receptor) and AT1bR (angiotensin type 1b receptor) and renal AR (androgen receptor) mRNA expression were elevated in vehicle-treated growth-restricted offspring, but not in G1-treated growth-restricted. Therefore, these data suggest that chronic estradiol supplementation prevents the increase in BP that develops in female growth-restricted offspring via actions that may involve its G-protein coupled receptor and the renin-angiotensin system.

Renal injury after uninephrectomy in male and female intrauterine growth-restricted aged rats.

Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.

Androgen Receptor Blockade Differentially Regulates Blood Pressure in Growth-Restricted Versus Ovarian Deficient Rats.

Low birth weight is associated with a greater prevalence of hypertension in women by age 60; yet, the mechanisms involved are unknown. We previously reported that hypertension in female growth-restricted offspring that is associated with early reproductive senescence and a shift in the testosterone-to-estradiol ratio at 12 months of age is abolished by AR (androgen receptor) blockade in conjunction with downregulation of renal AT1aR (angiotensin type 1a receptor) mRNA expression. These data suggest androgen-mediated activation of the renin-angiotensin system contributes to the pathogenesis of hypertension that develops in female growth-restricted offspring with aging. Thus, this study tested the hypothesis that androgen-mediated increased blood pressure is specific to female growth-restricted offspring. Control and growth-restricted rats underwent sham or ovariectomy at 10 months of age. Vehicle or flutamide (8 mg/kg/day; subcutaneous), an AR antagonist, was administered at 11.5 months of age for 2 weeks followed by measurement of blood pressure. Loss of ovarian hormones was associated with a 10 mm Hg increase in blood pressure in control compared with intact counterparts accompanied by a 1.8-fold increase in renal AT1aR mRNA expression. Treatment with flutamide had no effect on blood pressure or renal AT1aR mRNA expression in ovariectomized controls. Although blood pressure was significantly decreased in flutamide-treated ovariectomized growth-restricted, flutamide had no effect on the increase in renal AT1aR mRNA expression. Therefore, these findings suggest the effect of AR blockade on blood pressure is specific to intact growth-restricted offspring and that mechanisms of postmenopausal hypertension may differ between normal and low birth weight women.

Complications during pregnancy and fetal development: implications for the occurrence of chronic kidney disease.

INTRODUCTION: Numerous epidemiological studies indicate an inverse association between birth weight and the risk for chronic kidney disease. Areas covered: Historically, the first studies to address the developmental origins of chronic disease focused on the inverse relationship between birth weight and blood pressure. A reduction in nephron number was a consistent finding in low birth weight individuals and experimental models of developmental insult. Recent studies indicate that a congenital reduction in renal reserve in conjunction with an increase in blood pressure that has its origins in fetal life increases vulnerability to renal injury and disease. Expert commentary: Limited experimental studies have investigated the mechanisms that contribute to the developmental origins of kidney disease. Several studies suggest that enhanced susceptibility to renal injury following a developmental insult is altered by sex and age. More in-depth studies are needed to clarify how low birth weight contributes to enhanced renal risk, and how sex and age influence this adverse relationship.

Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats.

Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity, indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, SC for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin-converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin-angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats.