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Background: Sex differences play a critical role in the incidence and severity of cardiovascular diseases, whereby men are at a higher risk of developing cardiovascular disease compared to age-matched premenopausal women. Marked sex differences at the cellular and tissue level may contribute to susceptibility to cardiovascular disease and end-organ damage. In this study, we have performed an in-depth histological analysis of sex differences in hypertensive cardiac and renal injury in middle-aged stroke-prone spontaneously hypertensive rats (SHRSPs) to determine the interaction between age, sex and cell senescence., Methods: Kidneys, hearts and urine samples were collected from 6.5- and 8-month-old (Mo) male and female SHRSPs. Urine samples were assayed for albumin and creatinine content. Kidneys and hearts were screened for a suite of cellular senescence markers (senescence-associated β-galactosidase, p16 INK4a , p21, γH2AX). Renal and cardiac fibrosis was quantified using Masson's trichrome staining, and glomerular hypertrophy and sclerosis were quantified using Periodic acid-Schiff staining., Results: Marked renal and cardiac fibrosis, concomitant with albuminuria, were evident in all SHRSPs. These sequelae were differentially affected by age, sex and organ. That is, the level of fibrosis was greater in the kidney than the heart, males had greater levels of fibrosis than females in both the heart and kidney, and even a 6-week increase in age resulted in greater levels of kidney fibrosis in males. The differences in kidney fibrosis were reflected by elevated levels of cellular senescence in the kidney in males but not females. Senescent cell burden was significantly less in cardiac tissue compared to renal tissue and was not affected by age or sex., Conclusions: Our study demonstrates a clear sex pattern in age-related progression of renal and cardiac fibrosis and cellular senescence in SHRSP rats. A 6-week time frame was associated with increased indices of cardiac and renal fibrosis and cellular senescence in male SHRSPs. Female SHRSP rats were protected from renal and cardiac damage compared to age-matched males. Thus, the SHRSP is an ideal model to investigate the effects of sex and aging on organ injury over a short timeframe., (© 2023. The Author(s).)

A child with a congenital solitary functioning kidney (SFK) may develop kidney disease from early in life due to hyperfiltration injury. Previously, we showed in a sheep model of SFK that brief angiotensin-converting enzyme inhibition (ACEi) early in life is reno-protective and increases renal functional reserve (RFR) at 8 months of age. Here we investigated the long-term effects of brief early ACEi in SFK sheep out to 20 months of age. At 100 days gestation (term = 150 days) SFK was induced by fetal unilateral nephrectomy, or sham surgery was performed (controls). SFK lambs received enalapril (SFK+ACEi; 0.5 mg/kg, once daily, orally) or vehicle (SFK) from 4 to 8 weeks of age. At 8, 14 and 20 months of age urinary albumin excretion was measured. At 20 months of age, we examined basal kidney function and RFR via infusion of combined amino acid and dopamine (AA+D). SFK+ACEi resulted in lower albuminuria (∼40%) at 8 months, but not at 14 or 20 months of age compared with vehicle-SFK. At 20 months, basal GFR (∼13%) was lower in SFK+ACEi compared with SFK, but renal blood flow (RBF), renal vascular resistance (RVR) and filtration fraction were similar to SFK. During AA+D, the increase in GFR was similar in SFK+ACEi and SFK animals, but the increase in RBF was greater (∼46%) in SFK+ACEi than SFK animals. Brief ACEi in SFK delayed kidney disease in the short-term but these effects were not sustained long-term., (© 2023 The Author(s).)

A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT 2 R) has been considered as organ protective in many CVDs. However, there are limited AT 2 R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro 7 -AngIII, showed high selectivity for the AT 2 R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT 2 R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks' treatment (from weeks 5-8) with β-Pro 7 -AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro 7 -AngIII were attenuated by the AT 2 R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT 2 R-selective β-Pro 7 -AngIII, highlighting it as an important therapeutic that can target the AT 2 R to treat end-organ damage.

Background: Children born with a solitary functioning kidney (SFK) are predisposed to develop hypertension and kidney injury. Glomerular hyperfiltration and hypertrophy contribute to the pathophysiology of kidney injury. Angiotensin-converting enzyme inhibition (ACEi) can mitigate hyperfiltration and may be therapeutically beneficial in reducing progression of kidney injury in those with an SFK., Methods: SFK was induced in male sheep fetuses at 100 days gestation (term=150 days). Between 4 and 8 weeks of age, SFK lambs received enalapril (SFK+ACEi; 0.5mg/kg per day, once daily, orally) or vehicle (SFK). At 8 months, we examined BP, basal kidney function, renal functional reserve (RFR; GFR response to combined amino acid and dopamine infusion), GFR response to nitric oxide synthase (NOS) inhibition, and basal nitric oxide (NO) bioavailability (basal urinary total nitrate and nitrite [NOx])., Results: SFK+ACEi prevented albuminuria and resulted in lower basal GFR (16%), higher renal blood flow (approximately 22%), and lower filtration fraction (approximately 35%), but similar BP, compared with vehicle-treated SFK sheep. Together with greater recruitment of RFR (approximately 14%) in SFK+ACEi than SFK animals, this indicates a reduction in glomerular hyperfiltration-mediated kidney dysfunction. During NOS inhibition, the decrease in GFR (approximately 14%) was greater among SFK+ACEi than among SFK animals. Increased (approximately 85%) basal urinary total NOx in SFK+ACEi compared with SFK animals indicates elevated NO bioavailability likely contributed to improvements in kidney function and prevention of albuminuria., Conclusions: Brief and early ACEi in SFK is associated with reduced glomerular hyperfiltration-mediated kidney disease up to 8 months of age in a sheep model., (Copyright © 2022 by the American Society of Nephrology.)

The renin-angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang(1-7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life., (© 2016 Authors; published by Portland Press Limited.)

Background: Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep., Methods and Results: In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (N(ω)-nitro-l-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (P<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (PInteraction<0.01). Endothelial NO synthase and Ser-1177-phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep (P<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression (P<0.05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep (P<0.05)., Conclusions: Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation., (© 2014 American Heart Association, Inc.)

The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the "first hit" and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 +/- 1, 103 +/- 1, and 102 +/- 2 mmHg). On a high-salt diet, MAP increased 9.1 +/- 1.9 mmHg in HET1K mice (P < 0.05) and 5.4 +/- 0.9 mmHg in HET2K mice (P < 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype.

Maternal hypertension associated with renal disease is a common pregnancy complication. Previously, we have shown in a rabbit model of mild hypertension that offspring from hypertensive mothers have increased blood pressure as adults. In human pregnancy, hypertension has been associated with decreased utero-placental blood flow. The aim of this study was to determine placental blood flow (PBF) in mild (2-kidney-1-wrapped; 2K-1W) and moderate (2-kidney-2-wrapped; 2K-2W) rabbit models of maternal hypertension. We hypothesized that PBF would be inversely related to the severity of the hypertension. PBF and renal blood flow (RBF) were measured using microspheres on day 28 of a 32-day gestation, in normotensive (sham), 2K-1W, and 2K-2W hypertensive groups. Mean arterial pressure (MAP, approximately 7 mmHg, P < 0.05) was increased, and RBF ( approximately 35%, P < 0.05) was reduced in the 2K-1W and 2K-2W (MAP approximately 20 mmHg, P < 0.01; RBF approximately 53%, P < 0.05) groups compared with the sham group. In the 2K-1W group, PBF fell by approximately 12% (P = 0.08) and fetal-to-placental weight ratio increased by approximately 12% (P < 0.01) compared with the sham group, reflecting an increase in the functional capacity of the placenta to deliver nutrients to the fetus. In the 2K-2W group, PBF decreased approximately 51% (P < 0.05) compared with the sham group, without changes in placental efficiency. Thus, in late gestation, placental blood flow was significantly reduced in the moderate hypertension group, without accompanying changes in fetal or placental weight or placental efficiency. In contrast, mild hypertension resulted in an increase in placental efficiency, without significant changes in placental blood flow. These findings suggest that mild and moderate hypertension may alter placental delivery of nutrients via differing mechanisms dependent upon the severity of the hypertension.

Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD. [ABSTRACT FROM AUTHOR]

Previously we have shown that ovariectomised (OVX) female sheep have reduced renal function and elevated blood pressure from 6 months of age following fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days). In the current study we examined if in intact female sheep the onset of decline in renal function and elevation in blood pressure was prevented. Studies were performed at 1 year, 2 and 5 years of age. Following fetal uni-x at 100 days, intact female sheep had ∼30% reduction in glomerular filtration rate (GFR) at 1 year, which did not exacerbate with age (Ptreatment = 0.0001, Page = 0.7). In contrast renal blood flow was similar between the treatment groups at 1 year of age but had declined in the uni-x animals at 5 years of age (Ptreatment x age = 0.046). Interestingly, intact uni-x sheep did not develop elevations in arterial pressure until 2 years of age. Furthermore, uni-x animals had a similar capacity to respond to a cardiac challenge at 1 year and 2 years of age, however, cardiac functional reserve was significantly reduced compared to sham group at 5 years of age. Uni-x animals exhibited an increase in left ventricular dimensions at 5 years of age compared to the sham animals and compared to 2 years of age (Ptreatment <0.001, Ptreatment x age<0.001). In conclusion, the onset of renal dysfunction preceded the onset of hypertension in intact female uni-x sheep. Furthermore, this study showed that the intact females are protected from the impact of a reduced nephron endowment on cardiovascular health early in life as opposed to our findings in young male sheep and OVX uni-x female sheep. However, with ageing this protection is lost as evidenced by presence of left ventricular hypertrophy and impaired cardiac function in 5 year old uni-x female sheep. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) leads to a reduction in nephron endowment at birth and is linked to renal dysfunction in adulthood. The aim of the present study was to determine whether kidneys of IUGR rat offspring are more vulnerable to a secondary insult of hyperglycemia. IUGR was induced in Wistar-Kyoto rats by maternal protein restriction. At 24 wk of age, diabetes was induced in male IUGR and non-IUGR offspring by streptozotocin injection; insulin was injected daily to maintain blood glucose levels at either a mild (7-10 mmol/l; n=8/group) or a moderate (10-15 mmol/l; n=8/group) level. At 32 wk of age, renal function was assessed using ultrasound and [3H]inulin and [14C]para-aminohippurate clearance techniques. Conscious mean arterial blood pressure and heart rate were unchanged in IUGR offspring. Relative kidney length was increased significantly in IUGR offspring, and renal function was altered significantly; of importance, there was a significant increase in filtration fraction, indicative of glomerular hyperfiltration. Induction of hyperglycemia led to marked impairment of renal function. However, the response to hyperglycemia was not different between IUGR and non-IUGR offspring. Maintaining blood glucose levels at a mild hyperglycemic level led to marked improvement in all measures of renal function in IUGR and non-IUGR offspring. In conclusion, while the IUGR offspring showed evidence of hyperfiltration, the response to hyperglycemia was similar in IUGR and non-IUGR kidneys in adulthood. Importantly, maintaining blood glucose levels at a mild hyperglycemic level markedly attenuated the renal dysfunction associated with diabetes, even in IUGR offspring. [ABSTRACT FROM AUTHOR]

Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures. [ABSTRACT FROM AUTHOR]

Reduced nephron endowment is associated with development of renal and cardiovascular disease. We hypothesized this may be attributable to impaired sodium homoeostasis by the remaining nephrons. The present study investigated whether a nephron deficit, induced by fetal uninephrectomy at 100 days gestation (term=150 days), resulted in (i) altered renal sodium handling both under basal conditions and in response to an acute 0.9% saline load (50 ml · kg-1 of body weight · 30 min-1); (ii) hypertension and (iii) altered expression of renal channels/transporters in male sheep at 6 months of age. Uninephrectomized animals had significantly elevated arterial pressure (90.1± 1.6 compared with 77.8± 2.9 mmHg; P<0.001), while glomerular filtration rate and renal blood flow (per g of kidney weight) were 30% lower than that of the sham animals. Total kidney weight was similar between the groups. Renal gene expression of apical NHE3 (type 3 Na+ /H+ exchanger), ENaC (epithelium Na+ channel) β and γ subunits and basolateral Na+ /K+ ATPase β and γ subunits were significantly elevated in uninephrectomized animals, while ENaC a subunit expression was reduced. Urine flow rate and sodium excretion increased in both groups in response to salt loading, but this increase in sodium excretion was delayed by approximately 90 min in the uninephrectomized animals, while total sodium output was 12% in excess of the infused load (P<0.05). In conclusion, the present study shows that animals with a congenital nephron deficit have alterations in tubular sodium channels/transporters and cannot rapidly correct for variations in sodium intake probably contributing to the development of hypertension. This suggests that people born with a nephron deficit should be monitored for early signs of renal and cardiovascular disease. [ABSTRACT FROM AUTHOR]

The risk of developing many adult-onset diseases, including hypertension, type 2 diabetes, and renal disease, is increased in low-birth-weight individuals. A potential underlying mechanism contributing to the onset of these diseases is the formation of a low nephron endowment during development. Evidence from the human, as well as many experimental animal models, has shown a strong association between low birth weight and a reduced nephron endowment. However, other animal models, particularly those in which the mother is exposed to elevated glucocorticoids for a short period, have shown a 20-40% reduction in nephron endowment without discernible changes in the birth weight of offspring. Such findings emphasize that a low birth weight is one, but certainly not the only, predictor of nephron endowment and suggests reduced nephron endowment and risk of developing adult-onset disease, even among normal-birth-weight individuals. Recognition of the dissociation between birth weight and nephron endowment is important for future studies aimed at elucidating the role of a reduced nephron endowment in the developmental programming of adult disease. [ABSTRACT FROM AUTHOR]

Abstract: We compared the effects of tempol (300μmolkg−1 plus 300μmolkg−1 h−1, n =14) and candesartan (10μgkg−1 plus 10μgkg−1 h−1, n =14) on renal haemodynamics, excretory function, and responses to electrical stimulation of the renal nerves (RNS) in lean and obese rabbits under pentobarbitone anaesthesia. Depressor responses to tempol (−16±2mmHg) and candesartan (−12±1mmHg) were similar. Candesartan, but not tempol, significantly increased basal renal blood flow (RBF; +36±7%). Tempol, but not candesartan, significantly reduced glomerular filtration rate (GFR; −30±10%) and sodium excretion (UNaV; −44±14%). RNS induced frequency-dependent reductions in RBF (−20±3% at 1Hz), GFR (−28±6% at 1Hz) and UNaV (−55±6% at 1Hz). Candesartan blunted these responses. Tempol did not significantly alter RBF and GFR responses to RNS but blunted the UNaV response. Responses to RNS, and the effects of tempol and candesartan, were similar in lean compared with obese rabbits. Unlike candesartan, tempol did not induce renal vasodilatation, maintain GFR and UNaV during reductions in arterial pressure, or blunt neurally-mediated vasoconstriction. In conclusion, unlike the AT1-receptor antagonist candesartan, tempol does not blunt the effects of RNS on renal haemodynamic function. Furthermore, under the current experimental conditions superoxide appears to make little contribution to the actions of endogenous angiotensin II on baseline renal haemodynamics or excretory function, or their responses to RNS. [Copyright &y& Elsevier]