Renal Vascular Dysfunction Research Articles

Sex-specific effects of mild to moderate renal dysfunction on vascular endothelial function and large elastic artery stiffness

BACKGROUND: Cardiovascular disease (CVD) risk is elevated in patients with advanced chronic kidney disease (CKD). Vascular dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, is a key contributor to increased CVD risk in advanced CKD. Individuals with mild to moderately reduced renal function may also be at increased risk for CVD, but endothelial function and arterial stiffness are not well characterized in this group. Further, women with CKD have lower risk for CVD than men. Whether women are protected from renal dysfunction-related decreases in vascular function is unknown. PURPOSE: We sought to determine: i) whether individuals with mild to moderate renal dysfunction (MRD) have lower endothelial function and greater arterial (aortic) stiffness compared to healthy controls (HC) and ii) if the presence of vascular dysfunction in individuals with MRD is influenced by sex. METHODS & RESULTS: Fifty-nine adults were split into two groups based on renal function. Thirty-two adults (mean±SEM: 66±2 years; 16 women) were identified with MRD, characterized as an estimated glomerular filtration rate (eGFR) of 45-89 (CKD-EPI; 75.0±2.0 mL/min/1.73m2) and/or the presence of microalbuminuria (albumin: creatinine ratio between 30-300 mg/g). Twenty-seven adults (63±2 years; 13 women) were identified as HC with an eGFR >90 (CKD-EPI; 98.7±0.9 mL/min/1.73m2). Subject characteristics known to influence vascular function (e.g., blood pressure, cholesterol, blood glucose, etc.) were not different between groups (all p>0.05). Endothelial function, assessed by brachial artery flow mediated dilation, was not different between groups (MRD: 4.4±0.5%, HC: 4.6±0.5%, p=0.75). Aortic stiffness, assessed via carotid-femoral pulse wave velocity, also was not different (MRD: 950.7±50.6 cm/s, HC: 864.3±33.1 cm/s, p=0.18). When analyzed by sex, men with MRD had lower endothelial function (MRD: 2.8±0.4%, HC: 4.4±0.6%, p=0.04) and tended to have stiffer arteries (MRD: 879.0±42.7 cm/s, HC: 787.7±35.5 cm/s, p=0.11) compared to HC men. In women with MRD, there were no differences in endothelial function (MRD: 5.9±0.8%, HC: 4.8±0.8%, p=0.36) or aortic stiffness (MRD: 1022.3±89.9 cm/s, HC: 953.6±49.4 cm/s, p=0.55) versus HC women. CONCLUSIONS: Men with MRD exhibit vascular dysfunction, while women appear to be protected from MRD-related vascular dysfunction. The lower risk of CVD in women versus men with CKD may, in part, be due to resistance against renal dysfunction-related vascular dysfunction. NIH K01DK115524 to MJR; 5T32DK007135-46 to KOM; K01HL153326 to DHC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Postoperative association between impaired renal function and vascular dysfunction in liver transplant recipients.

Postoperative association between impaired renal function and vascular dysfunction in liver transplant recipients.

The NO-cGMP-K+ Channel Pathway Participates in Diuretic and Cardioprotective Effects of Blutaparon portulacoides in Spontaneously Hypertensive Rats.

Blutaparon portulacoides is a Brazilian plant species that is widely used in folk medicine. The present study investigated the role of an aqueous extract of B. portulacoides against hypertension in spontaneously hypertensive rats. The aqueous extract of B. portulacoides was obtained from the whole plant. Its chemical profile was analyzed by ultraperformance liquid chromatography-tandem mass spectrometry. The acute toxicity of the aqueous extract of B. portulacoides was evaluated in female Wistar rats. Male 6-month-old spontaneously hypertensive rats then received the aqueous extract of B. portulacoides (30, 100, and 300 mg/kg), hydrochlorothiazide (25 mg/kg), or vehicle once daily for 28 days. On days 1, 14, and 28, the diuretic effects of the aqueous extract of B. portulacoides were evaluated. The role of prostaglandins and the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway in the diuretic activity of the aqueous extract of B. portulacoides was also investigated. At the end of the treatment, hepatic and renal biochemical markers, serum nitrotyrosine, malondialdehyde, nitrite, and aldosterone levels, and angiotensin-converting enzyme activity were measured. The electrocardiographic profile, blood pressure, and renal vascular reactivity were also assessed. The heart, kidneys, and liver were collected to determine relative organ weight, histopathology, and cardiac morphometry. Caffeic acid, ferulic acid, and several flavonoids were identified in the aqueous extract of B. portulacoides. No signs of toxicity were observed. Prolonged treatment with the aqueous extract of B. portulacoides (300 mg/kg) induced significant diuretic activity by activating the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway. These effects reduced blood pressure and oxidative stress and prevented renal vascular dysfunction and left ventricular hypertrophy that was induced by hypertension. Overall, the present data suggest that the aqueous extract of B. portulacoides has important diuretic and cardioprotective effects by activation of the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway.

DHHC21 deficiency attenuates renal dysfunction during septic injury

Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21dep/dep) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.

GLUCOCORTICOID EXCESS INDUCES NON-DIPPING BLOOD PRESSURE AND RENAL VASCULAR DYSFUNCTION

Abstract Objective: Blood pressure (BP) abnormalities such as loss/attenuation of nocturnal BP dip (non-dipping) increase cardiovascular risk. The mechanisms underlying non-dipping are not clear, but renal and vascular dysfunction has been implicated. People with abnormal glucocorticoid (GC) homeostasis, such as in Cushing's syndrome, often display non-dipping BP therefore, here we investigated the contribution of GCs to BP rhythmicity. Design and method: The effect of GC excess, driven by ACTH infusion, on BP and plasma GC rhythmicity was examined in adult male C57BL/6J mice. Radiotelemetry was used to measure BP longitudinally before and after ACTH infusion (2.5 mg/day for 14days via minipump). Diurnal plasma GCs was measured by ELISA. Diurnal renal vascular function was investigated ex vivo by wire myography in isolated renal arteries from separate cohorts of mice either control or ACTH-treated collected between 7–8AM (day) or 7–8PM (night). Vascular reactivity to vasoconstrictor phenylephrine (PHE), endothelium-dependent acetylcholine (ACh) and endothelium-independent sodium nitroprusside (SNP) vasodilators was assessed. Data are mean ± SD. Results: After 5days of baseline measurements, 24-hour systolic BP (SBP) was 123.8 ± 4.2 mmHg and 24-hour diastolic BP (DBP) was 96.2 ± 5.6 mmHg. The day:night SBP and DBP variation was 12.8 ± 4.5 mmHg and 12.3 ± 4.8 mmHg, respectively. ACTH-excess increased 24-hour SBP to 133.8 ± 1.7 mmHg and 24-hour DBP to 101.4 ± 2.1 mmHg. The day:night SBP and DBP variation was reduced to 0.6 ± 7.2 mmHg (p = 0.0166) and 2.4 ± 9.6 mmHg (p = 0.0235), respectively. Day:night activity count during BP measurements was similar before and after ACTH infusion. Diurnal plasma GCs was increased following ACTH infusion, compared with baseline (p < 0.0001). Furthermore, ACTH-excess flipped the diurnal rhythm of GC, so the day plasma GC concentration is higher than the night. Day control renal arteries showed a trend for an increase in sensitivity to PHE (p = 0.0578) and SNP (p = 0.0795), with no changes in ACh (p = 0.1299), compared with night control renal arteries. ACTH-excess caused no differences in day and night responses to PHE (p = 0.5526), ACh (p = 0.1169), and SNP (p = 0.9466). ACTH-excess caused renal vascular dysfunction, compared with controls, causing a significant reduction in sensitivity to PHE (p = 0.0005), ACh (p = 0.0128) and SNP (p = 0.0002). Conclusions: These data show that chronic GC induces non-dipping BP and renal vascular dysfunction.

Vitamin D Deficiency Cause Gender Specific Alterations of Renal Arterial Function in a Rodent Model.

Vitamin D deficiency shows positive correlation to cardiovascular risk, which might be influenced by gender specific features. Our goal was to examine the effect of Vitamin D supplementation and Vitamin D deficiency in male and female rats on an important hypertension target organ, the renal artery. Female and male Wistar rats were fed with Vitamin D reduced chow for eight weeks to induce hypovitaminosis. Another group of animals received normal chow with further supplementation to reach optimal serum vitamin levels. Isolated renal arteries of Vitamin D deficient female rats showed increased phenylephrine-induced contraction. In all experimental groups, both indomethacin and selective cyclooxygenase-2 inhibition (NS398) decreased the phenylephrine-induced contraction. Angiotensin II-induced contraction was pronounced in Vitamin D supplemented males. In both Vitamin D deficient groups, acetylcholine-induced relaxation was impaired. In the female Vitamin D supplemented group NS398, in males the indomethacin caused reduced acetylcholine-induced relaxation. Increased elastic fiber density was observed in Vitamin D deficient females. The intensity of eNOS immunostaining was decreased in Vitamin D deficient females. The density of AT1R staining was the highest in the male Vitamin D deficient group. Although Vitamin D deficiency induced renal vascular dysfunction in both sexes, female rats developed more extensive impairment that was accompanied by enzymatic and structural changes.

Changes in the renal function after acute mercuric chloride exposure in the rat are associated with renal vascular endothelial dysfunction and proximal tubule NHE3 inhibition

Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 μg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. “In vitro” experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing “in vivo” stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.

Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Kefir Peptides on Salt-Induced Renal Vascular Damage and Dysfunction in Aged Stroke-Prone Spontaneously Hypertensive Rats.

The increased prevalence of renal dysfunction and chronic kidney disease (CKD) and the high costs and poor outcomes of treatment are a significant health issue. The consequence of chronic high blood pressure is the increased prevalence of target organ end-stage renal disease, which has been proven to be a strong independent risk factor for adverse cardiovascular disease. A previous study showed that kefir products have anti-inflammatory and anti-hypertensive activities and immunological modulation functions. However, no data regarding the beneficial effects of kefir peptides (KPs) on salt-induced renal damage or related kidney diseases are available. In this study, KPs were orally administered to aged salt-induced stroke-prone spontaneously hypertensive (SHRSP) rats, and the effects of KPs against inflammation and oxidative stress and their ability to protect against renal dysfunction were evaluated. Fifty-five-week-old SHRSP rats under induction with 1% NaCl in drinking water for 4 weeks showed multiple renal injuries with increased renal inflammation, fibrosis, oxidative stress, tubular atrophy, and glomerulosclerosis. In contrast, oral gavage with KPs reduced the urine protein to creatinine (UPC) ratio, the fractional excretion of electrolytes (FeNa and FeCl), extracellular matrix deposition, and the interstitial fibrotic α-smooth muscle actin (α-SMA) levels in salt-induced SHRSP rats. The renal infiltration of inflammatory cells; the release of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), and the cytokine nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) and transforming growth factor-β (TGF-β); the reactive oxygen species (ROS) levels; and histopathological lesions were also decreased in salt-induced SHRSP rats. Furthermore, KP treatment significantly increased the renal superoxide dismutase (SOD) activity and the glomerular filtration rate (GFR), which exerted potent protection against salt-induced chronic kidney disease in SHRSP rats. The results of this study suggest that KPs ameliorate salt-induced renal damage, tubular atrophy, and glomerular dysfunction through anti-inflammatory, antioxidative stress, and antifibrotic activities, and might be a promising protective agent against high salt-induced renovascular-related diseases.

Anti-Inflammatory, Antioxidant and Antifibrotic Effects of Kefir Peptides on Salt-Induced Renal Vascular Damage and Dysfunction in Aged Stroke-Prone Spontaneously Hypertensive Rats

Anti-Inflammatory, Antioxidant and Antifibrotic Effects of Kefir Peptides on Salt-Induced Renal Vascular Damage and Dysfunction in Aged Stroke-Prone Spontaneously Hypertensive Rats

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial

BackgroundType 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD.MethodsThe PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0–9.0%) and established CKD (30 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m2 or ≥ 45 mL/min/1.73 m2), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks.DiscussionPROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials.Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).

Caracterización clínica y microbiológica de pacientes con pie diabético que requieren hospitalización en alta complejidad. Serie de casos

BackgroundInfected diabetic foot is a frequent complication of diabetes and a marker of patient deterioration. There is little information in Colombia on the characteristics of patients that enter the highly complex emergency services with this condition and their outcomes, such as amputation and microbiological profile. MaterialsCase series of patients admitted to the emergency department of Pablo Tobón Uribe Hospital whose main consultation was infected diabetic foot. The medical records were retrospectively analysed and descriptive statistical tools were used to characterise the population, as well as the variables related to diagnosis, treatment, and early in-hospital outcomes. ResultsBetween January 2009 and December 2013, 118 patients with 145 ulcers due to an infected diabetic foot were admitted. The HbA1c was> 6.5 in 90%, and 52% had renal dysfunction, 51% with peripheral arterial disease, and 57% had ulcers grade 3 or higher in the Wagner classification. The infection was polymicrobial in 63%, and 58% required amputation, with 62% of amputations being classed as minor. Mortality was 10%, and mortality attributable to diabetic foot infection or complications derived from amputation was 1.7%. DiscussionPatients with diabetic foot admitted to the emergency room of a high complexity hospital in Colombia have an advanced systemic disease, related to renal and peripheral vascular dysfunction, and serious local injuries with advanced bone and joint involvement. Given the severity of these conditions, the prevalence of major amputations may be higher than that reported in the literature.Evidence Level: IV

MicroRNA and mRNA analysis of angiotensin II-induced renal artery endothelial cell dysfunction.

Continuous activation of angiotensin II (Ang II) induces renal vascular endothelial dysfunction, inflammation and oxidative stress, all of which may contribute to renal damage. MicroRNAs (miRs/miRNAs) play a crucial regulatory role in the pathogenesis of hypertensive nephropathy (HN). The present study aimed to assess the differential expression profiles of potential candidate genes involved in Ang II-induced rat renal artery endothelial cell (RRAEC) dysfunction and explore their possible functions. In the present study, the changes in energy metabolism and autophagy function in RRAECs were evaluated using the Seahorse XF Glycolysis Stress Test and dansylcadaverine/transmission electron microscopy following exposure to Ang II. Subsequently, mRNA-miRNA sequencing experiments were performed to determine the differential expression profiles of mRNAs and miRNAs. Integrated bioinformatics analysis was applied to further explore the molecular mechanisms of Ang II on endothelial injury induced by Ang II. The present data supported the notion that Ang II upregulated glycolysis levels and promoted autophagy activation in RRAECs. The sequencing data demonstrated that 443 mRNAs and 58 miRNAs were differentially expressed (DE) in response to Ang II exposure, where 66 mRNAs and 55 miRNAs were upregulated, while 377 mRNAs and 3 miRNAs were downregulated (fold change >1.5 or <0.67; P<0.05). Functional analysis indicated that DE mRNA and DE miRNA target genes were mainly associated with cell metabolism (metabolic pathways), differentiation (Th1 and Th2 cell differentiation), autophagy (autophagy-animal and autophagy-other) and repair (RNA-repair). To the best of the authors' knowledge, this is the first report on mRNA-miRNA integrated profiles of Ang II-induced RRAECs. The present results provided evidence suggesting that the miRNA-mediated effect on the ‘mTOR signaling pathway’ might play a role in Ang II-induced RRAEC injury by driving glycolysis and autophagy activation. Targeting miRNAs and their associated pathways may provide valuable insight into the clinical management of HN and may improve patient outcome.

A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease.

The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.

MicroRNA-200c-3p inhibits proliferation and migration of renal artery endothelial cells by directly targeting ZEB2

Continuous activation of angiotensin II (Ang II) induces renal vascular endothelial dysfunction, inflammation, and oxidative stress, all of which may contribute to renal damage. It is well established that microRNAs (miRNAs) play crucial regulatory roles in the pathogenesis of hypertensive renal damage. However, the detailed mechanisms and regulatory roles of miRNAs as therapeutic targets underlying Ang II-induced renal artery endothelial cell dysfunction in hypertensive renal damage have yet to be fully elucidated. The present study aimed to explore the expression status and putative role of miRNA-200c-3p in mediating the progression of hypertensive renal damage. We carried out real-time quantitative PCR (RT-qPCR) to detect the expression of miRNA-200c-3p in rat renal artery endothelial cells (RRAECs) induced by Ang II. MTT and transwell assays were utilized to evaluate the effects of miRNA-200c-3p on cell proliferation and migration, respectively. The present results revealed that the expression of miRNA-200c-3p was significantly upregulated in RRAECs exposed to Ang II compared with that of normal cells. miRNA-200c-3p overexpression markedly inhibited cell proliferation and migration of Ang II-induced RRAECs. Furthermore, bioinformatics predictions and dual-luciferase reporter assays indicated that zinc finger E-box-binding homeobox 2 (ZEB2) was a direct target gene of miRNA-200c-3p and that ZEB2 expression was inversely correlated with the levels of miRNA-200c-3p in RRAECs after exposure to Ang II. The effects of ZEB2 silencing were similar to the inhibitory effects observed following miRNA-200c-3p overexpression, and recovered ZEB2 expression reversed the anti-proliferative and anti-migratory influence of miRNA-200c-3p upregulation in RRAECs induced by Ang II. The present study indicated that miRNA-200c-3p might suppress the proliferation and migration of Ang II-induced RRAECs by targeting ZEB2. The miRNA-200c-3p/ZEB2 axis will provide valuable insights into the clinical management of hypertension-related kidney disease.

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system.

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.

Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H2O2.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH–dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2–mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.

When Less or More Isn't Enough: Renal Maldevelopment Arising From Disequilibrium in the Renin-Angiotensin System.

Environmental and nutritional factors during fetal and neonatal life can have long-lasting effects on renal functions and physiology and susceptibility to kidney disease in adulthood. All components of the renin-angiotensin system (RAS) are highly expressed in the kidneys during the period of renal development. The RAS plays a central role in the regulation of various cellular growth factors and stimulates adhesion molecules and cellular migration. The use of antagonists of this system during fetal development represents a major risk factor for hypertension, renal vascular dysfunction, and kidney medulla atrophy in adulthood. The inappropriate activation of the RAS by vitamin D (VitD) deficiency has been studied in recent years. Clinical and experimental studies have demonstrated an inverse relationship between circulating VitD levels and blood pressure, plasma and renin activity, and an increase in angiotensin II and the receptor AT1. These data raise new questions about the importance of the integrity of the RAS during development since RAS pathway inhibitors and VitD deficiency have opposing functions. This is a literature review on the possible mechanisms by which antagonists of the RAS and VitD deficiency during fetal development provoke disturbances in kidney structure and function. Potential mechanisms are presented and discussed, and the possible pathways by which an imbalanced maternal RAS may negatively impact fetal development and have consequences in adulthood are also explored.

SAT-114 ABERRANT RENAL AND MESENTERIC HEMODYNAMIC RESPONSES TO A HIGH SALT DIET AND BLOOD PRESSURE SALT-SENSITIVITY ARE ABOLISHED IN CONSOMIC SS.BN1 vs. DAHL SS RATS

The contribution of renal vs. systemic vascular dysfunction in the pathogenesis of salt-sensitive (SS) hypertension is a topic of considerable debate. The Dahl salt-sensitive (SS) rat is commonly used to investigate the genetic and pathophysiologic basis of SS hypertension. A consomic panel of rats in which individual chromosomes from the salt-resistant Brown-Norway (BN) rat are introgressed into the Dahl SS background have shown that genes on rat chromosome 1 play an important role in the pathogenesis SS hypertension. Here, we investigated renal injury as well as renal and mesenteric hemodynamics in conscious Dahl SS vs. consomic SS.BN1 rats fed low and high salt diets. Systolic blood pressure (BP, 24 hrs/day via telemetry), proteinuria and renal injury were assessed in 10-12 week old SS, BN and SS.BN1 rats fed a 0.4% or 4.0% NaCl diet for 3 weeks. Proteinuria and renal injury were also assessed in naïve 10-12 week vs. 5-6 month old SS, BN and SS.BN1 rats maintained on a 0.4% NaCl diet. BP (telemetry) and either renal blood flow (RBF, Transonic flow probe) or mesenteric blood flow (MBF, Transonic flow probe) were assessed (200 Hz, 2 hrs/day) in conscious 10-12 week old SS vs. SS.BN1 rats during 3 days of 0.4% NaCl feeding and during 5 days of 4.0% NaCl feeding. Finally, glomerular filtration rate (GFR) was assessed via creatinine clearance in 10-12 week old SS vs. SS.BN1 rats on a 0.4% NaCl diet and after 3 weeks of a 4.0% NaCl diet. SS hypertension was minimal and comparable in SS.BN1 and BN rats. In contrast, SS rats developed substantial increases in BP and proteinuria on a high salt diet. Glomerular and tubulointerstitial injury was prevalent in SS rats and correlated strongly with systolic BP. Significant renal injury and proteinuria was observed even in 10-12 week old SS, but not BN or SS.BN1, rats maintained on a 0.4% diet. Moreover, numerous abnormal tubules exhibiting enlarged hyperchromatic nuclei, non-isometric tubular vacuolization, loss of brush border and epithelial cell sloughing were observed in 10-12 week old SS rats. Frozen sections stained with H&E of kidneys from 10-12 week old SS rats showed protein plug formations within numerous tubule lumens. The magnitude of renal injury and proteinuria was substantially greater in 5-6 month old SS, but not BN or SS.BN1, rats fed a 0.4% NaCl diet as compared to respective 10-12 week old rats. When administered a 4.0% NaCl diet, SS.BN1 rats exhibited a significant decrease in renal vascular resistance (RVR) and increase in RBF but no change in mesenteric vascular resistance (MVR) or MBF. In contrast, RVR tended to increase and RBF decrease in SS rats fed a 4.0% high salt diet. Moreover, MVR significantly increased and MBF decreased in SS rats fed a high salt diet. GFR (normalized to body weight) tended to increase in SS.BN1 rats fed a high salt diet but no change was observed in SS rats. Introgression of chromosome 1 from the salt-resistant BN rat into the SS rat prevents SS hypertension. Such prevention is likely due, in large part, to a normal renal parenchyma and the ability of the renal vasculature to dilate and GFR to increase in response to a high salt diet. Moreover, the absence of aberrant increases in MVR during high salt feeding in SS.BN1 rats may further contribute to their resistance to SS hypertension.

Mechanisms of Salt‐Sensitive Hypertension in a Mouse Model of ACTH‐Dependent Cushing Syndrome

Salt‐sensitive blood pressure (BP) reflects underlying renal and vascular (endothelial) dysfunction. People with abnormal glucocorticoid homeostasis, such as in Cushing syndrome and obesity, are often salt‐sensitive but the underlying mechanisms are not clearly defined1,2. Here, we used a mouse model to examine the effect of ACTH excess on blood pressure and salt‐sensitivity. To test this, radio telemetry was used to track BP longitudinally and measure the effect of high salt diet before and after chronic ACTH treatment in C57BL/6J mice (n=6). Data are mean ± SD. After 7 days of baseline measurements, mean BP was 105.8 ± 6.5mmHg before being placed on a high salt diet (3 % Na+ by weight) for a further 7 days. BP increased ~12 mmHg over the first 3 days before declining to 113.1 ± 7.2mmHg. BP returned to 107.7 ± 10.4mmHg, similar to baseline, after a 5‐day washout period. Mice were then treated with ACTH (2.5μg/day). ACTH increased mean BP to 115.5 ± 5.0mmHg with a flattening of the diurnal rhythm following 13 days infusion. When placing these mice on a high salt diet, mean BP increased and stabilised to 136.1 ± 13.4mmHg after 14 days. These data show that chronic ACTH excess contributes to salt‐sensitivity. To investigate potential mechanisms of salt‐sensitivity, the acute pressure natriuresis (PN) response of renal artery function were examined in separate cohorts of mice treated with either vehicle or ACTH (2.5μg/day; n=6 per group) for 14 days. PN response was induced in anaesthesised mice (120mg/kg Inactin) by sequential arterial ligation. BP increased ~40mmHg following ligations in both vehicle and ACTH groups. In vehicle‐treated mice, fractional sodium excretion increased from 0.2 ± 0.2 to 5.0 ± 4.2μmol/min. The natriuretic response was significantly blunted in ACTH‐treated mice, reaching 2.1 ± 1.1μmol/min at its peak. We next investigated vascular function in ACTH‐excess ex vivo by wire myography in isolated mesenteric and renal arteries. Vascular reactivity to phenylephrine (PHE), acetylcholine (ACh) and sodium nitroprusside (SNP) was assessed. ACTH‐excess caused vascular dysfunction in the renal artery but not in the mesenteric artery. ACTH‐excess resulted in a reduction in sensitivity to vasoconstrictor PHE (p=0.0005) and endothelium dependent (ACh) and endothelium independent (SNP) vasodilators (p=0.0128 and p=0.0002, respectively). These data show that chronic glucocorticoid excess contributes to salt‐sensitivity with potential mechanisms behind this being impairment of the acute natriuretic and diuretic response to increased BP and renal vascular dysfunction.Support or Funding InformationSupported by British Heart Foundation PhD studentships FS/16/54/32730 &amp; FS/15/63/32033.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A6507 Renal fibrosis and vascular dysfunction in BPH/2J genetically hypertensive mice

A6507 Renal fibrosis and vascular dysfunction in BPH/2J genetically hypertensive mice