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Acta Physiologica (Oxford, England) Apr 2023Recruitment of renal functional reserve (RFR) with amino acid loading increases renal blood flow and glomerular filtration rate. However, its effects on renal cortical...
AIM
Recruitment of renal functional reserve (RFR) with amino acid loading increases renal blood flow and glomerular filtration rate. However, its effects on renal cortical and medullary oxygenation have not been determined. Accordingly, we tested the effects of recruitment of RFR on renal cortical and medullary oxygenation in non-anesthetized sheep.
METHODS
Under general anesthesia, we instrumented 10 sheep to enable subsequent continuous measurements of systemic and renal hemodynamics, renal oxygen delivery and consumption, and cortical and medullary tissue oxygen tension (PO ). We then measured the effects of recruitment of RFR with an intravenous infusion of 500 ml of a clinically used amino acid solution (10% Synthamin® 17) in the non-anesthetized state.
RESULTS
Compared with baseline, Synthamin® 17 infusion significantly increased renal oxygen delivery mean ± SD maximum increase: (from 0.79 ± 0.17 to 1.06 ± 0.16 ml/kg/min, p < 0.001), renal oxygen consumption (from 0.08 ± 0.01 to 0.15 ± 0.02 ml/kg/min, p < 0.001), and glomerular filtration rate (+45.2 ± 2.7%, p < 0.001). Renal cortical tissue PO increased by a maximum of 26.4 ± 1.1% (p = 0.001) and medullary tissue PO increased by a maximum of 23.9 ± 2.8% (p = 0. 001).
CONCLUSIONS
In non-anesthetized healthy sheep, recruitment of RFR improved renal cortical and medullary oxygenation. These observations might have implications for the use of recruitment of RFR for diagnostic and therapeutic purposes.
Topics: Sheep; Animals; Oxygen; Kidney; Renal Circulation; Acute Kidney Injury; Hemodynamics; Oxygen Consumption
PubMed: 36598336
DOI: 10.1111/apha.13919 -
Physiological Genomics Feb 2022Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer's disease. Previous genetic studies... (Review)
Review
Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer's disease. Previous genetic studies have nominated hundreds of genes linked to hypertension, and renal and cognitive diseases. Some have been advanced as candidate genes by showing that they can alter blood pressure or renal and cerebral vascular function in knockout animals; however, final validation of the causal variants and underlying mechanisms has remained elusive. This review chronicles 40 years of work, from the initial identification of adducin (ADD) as an ACTIN-binding protein suggested to increase blood pressure in Milan hypertensive rats, to the discovery of a mutation in ADD1 as a candidate gene for hypertension in rats that were subsequently linked to hypertension in man. More recently, a recessive K572Q mutation in ADD3 was identified in Fawn-Hooded Hypertensive (FHH) and Milan Normotensive (MNS) rats that develop renal disease, which is absent in resistant strains. ADD3 dimerizes with ADD1 to form functional ADD protein. The mutation in ADD3 disrupts a critical ACTIN-binding site necessary for its interactions with actin and spectrin to regulate the cytoskeleton. Studies using KO and transgenic strains, as well as a genetic complementation study in FHH and MNS rats, confirmed that the K572Q mutation in ADD3 plays a causal role in altering the myogenic response and autoregulation of renal and cerebral blood flow, resulting in increased susceptibility to hypertension-induced renal disease and cerebral vascular and cognitive dysfunction.
Topics: Animals; Blood Pressure; Calmodulin-Binding Proteins; Cognitive Dysfunction; Disease Models, Animal; Genetic Predisposition to Disease; Homeostasis; Humans; Hypertension; Hypertension, Renal; Mutation; Nephritis; Precision Medicine; Rats; Renal Circulation
PubMed: 34859687
DOI: 10.1152/physiolgenomics.00119.2021 -
American Journal of Physiology. Renal... Aug 2018Animal models of chronic kidney disease (CKD) are critical for understanding its pathophysiology and for therapeutic development. The cardiovascular and renal anatomy...
Animal models of chronic kidney disease (CKD) are critical for understanding its pathophysiology and for therapeutic development. The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. This study aimed to develop a novel translational model of CKD that mimics the pathological features of CKD in humans. CKD was induced in seven domestic pigs by bilateral renal artery stenosis and diet-induced dyslipidemia. Animals were observed for a total of 14 wk. Renal hemodynamics and function were quantified in vivo using multi-detector CT after 6, 10, and 14 wk of CKD. Urine and blood were collected at each time-point, and blood pressure was continuously measured (telemetry). After completion of in vivo studies, pigs were euthanized, kidneys were removed, and microvascular (MV) architecture (μCT), markers of renal injury, inflammation, and fibrosis were evaluated ex vivo. Additional pigs were used as controls ( n = 7). Renal blood flow and glomerular filtration were reduced by 50% in CKD, accompanied by hypertension and elevated plasma creatinine, albumin-to-creatinine ratio and increased urinary KIM-1 and NGAL, suggesting renal injury. Furthermore, 14 wk of CKD resulted in cortical and medullary MV remodeling and loss, inflammation, glomerulosclerosis, tubular atrophy, and tubule-interstitial fibrosis compared with controls. The current study characterizes a novel model of CKD that mimics several of the pathological features observed in human CKD, irrespective of the etiology. Current approaches only slow rather than halt CKD progression, and this novel model may offer a suitable platform for the development of new treatments in a translational fashion.
Topics: Animals; Biomarkers; Diet, High-Fat; Disease Models, Animal; Disease Progression; Dyslipidemias; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Renal Artery Obstruction; Renal Circulation; Renal Insufficiency, Chronic; Species Specificity; Sus scrofa; Time Factors; Translational Research, Biomedical
PubMed: 29693449
DOI: 10.1152/ajprenal.00063.2018 -
PloS One 2014Renal vascular responses to pregnancy have frequently been studied, by investigating renal vascular resistance (RVR), renal flow, glomerular filtration rate (GFR), and... (Meta-Analysis)
Meta-Analysis Review
Renal vascular responses to pregnancy have frequently been studied, by investigating renal vascular resistance (RVR), renal flow, glomerular filtration rate (GFR), and renal artery responses to stimuli. Nonetheless, several questions remain: 1. Which vasodilator pathways are activated and to what extent do they affect RVR, renal flow and GFR across species, strains and gestational ages, 2. Are these changes dependent on renal artery adaptation, 3. At which cellular level does pregnancy affect the involved pathways? In an attempt to answer the questions raised, we performed a systematic review and meta-analysis on animal data. We included 37 studies (116 responses). At mid-gestation, RVR and GFR change to a similar degree across species and strains, accompanied by variable change in renal flow. At least in rats, changes depend on NO activation. At late gestation, changes in RVR, renal flow and GFR vary between species and strains. In rats, these changes are effectuated by sympathetic stimulation. Overall, renal artery responsiveness to stimuli is unaffected by pregnancy, except for Sprague Dawley rats in which pregnancy enhances renal artery vascular compliance and reduces renal artery myogenic reactivity. Our meta-analysis shows that: 1. Pregnancy changes RVR, renal flow and GFR dependent on NO-activation and sympathetic de-activation, but adjustments are different among species, strains and gestational ages; 2. These changes do not depend on adaptation of renal artery responsiveness; 3. It remains unknown at which cellular level pregnancy affects the pathways. Our meta-analysis suggests that renal changes during pregnancy in animals are qualitatively similar, even in comparison to humans, but quantitatively different.
Topics: Animals; Female; Glomerular Filtration Rate; Kidney; Pregnancy; Pregnancy, Animal; Rats; Renal Artery; Renal Circulation; Vascular Resistance
PubMed: 25386682
DOI: 10.1371/journal.pone.0112084 -
Journal of Applied Physiology... Jan 2021One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly,...
One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; -10, -20, and -30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured ( = 13) as LBNP was instituted. LBNP significantly reduced RBV ( = 0.041) at -30 mmHg of LBNP (Δ-8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla. In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.
Topics: Humans; Kidney; Lower Body Negative Pressure; Renal Circulation; Sympathetic Nervous System; Vasoconstriction; Young Adult
PubMed: 33211597
DOI: 10.1152/japplphysiol.00739.2019 -
Internal Medicine (Tokyo, Japan) Apr 2020
Topics: Atherosclerosis; Humans; Kidney; Renal Circulation
PubMed: 31866627
DOI: 10.2169/internalmedicine.4145-19 -
Journal of the American Heart... Sep 2018Background The tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and...
Background The tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib-induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib-treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib-induced hypertension. Methods and Results Arterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib-treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib-treated rats. Nitrate supplementation did not mitigate sunitinib-induced hypertension. Endothelium-dependent reductions in renal vascular resistance were similar in control and sunitinib-treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib-treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α-subunit protein abundance were less in sunitinib-treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15-20 mm Hg in sunitinib-treated rats. Conclusions Renal cortical sGC is downregulated in the presence of intact endothelium-dependent renal vascular resistance regulation in developing sunitinib-induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib-induced hypertension.
Topics: Animals; Blood Pressure; Disease Models, Animal; Down-Regulation; Guanylate Cyclase; Hypertension; Kidney; Male; Rats; Rats, Wistar; Renal Circulation; Sunitinib; Vascular Resistance
PubMed: 30371202
DOI: 10.1161/JAHA.118.009557 -
Biomedicine & Pharmacotherapy =... Sep 2021Eucommia ulmoides leaves are used as Tochu tea, which has a blood pressure lowering effect of unknown mechanism.
INTRODUCTION
Eucommia ulmoides leaves are used as Tochu tea, which has a blood pressure lowering effect of unknown mechanism.
PURPOSE AND METHODS
The effects of Tochu tea and its component, geniposidic acid, on blood pressure and renal hemodynamics were investigated in Dahl salt-sensitive (DS) rats received 1% saline solution from 4 weeks of age. At 9 weeks of age, 1% saline alone (DSHS), Tochu tea extract added 1% saline (DSHS+T), or geniposidic acid added 1% saline (DSHS+G) was administered for another 4 weeks. DS rats fed with tap water were used as controls (DSLS). At 13 weeks, the blood pressure, the renal plasma flow (RPF) and the renal NADPH oxidase, endothelial nitric oxide synthase (eNOS) were examined.
RESULTS
Blood pressure in DSHS rats was significantly increased in comparison to DSLS (144 vs. 196 mmHg, p < 0.01), and was significantly reduced in DSHS+T (158 mmHg) and DSHS+G (162 mmHg) rats. RPF in DSHS+T rats was significantly higher than in DSHS rats (p < 0.05). The expression of NADPH oxidase in DSHS rats was enhanced in comparison to DSLS rats; however, it was suppressed in DSHS+T and DSHS+G rats, and the NO production by eNOS was increased; thus, RPF was improved. The urinary Na excretion in DSHS rats was higher than that in DSLS rats; however it was further increased in DSHS+T rats without changes in the tubular Na transporters.
CONCLUSION
Tochu tea and geniposidic acid suppressed NADPH oxidase, increased eNOS, and improved blood pressure and renal hemodynamics.
Topics: Animals; Antihypertensive Agents; Blood Pressure; Cytokines; Eucommiaceae; Iridoid Glucosides; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Plant Extracts; Plant Leaves; Rats; Rats, Inbred Dahl; Renal Circulation
PubMed: 34328117
DOI: 10.1016/j.biopha.2021.111901 -
Journal of the American Society of... May 2020Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular... (Review)
Review
Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.
Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1 and HIF-2)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2 signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.
Topics: Adenylate Kinase; Autophagy; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endoplasmic Reticulum Stress; Humans; Hypoglycemic Agents; Ion Transport; Kidney Tubules; Metformin; Mitochondria; Nutrients; Oxidative Stress; Oxygen; Oxygen Consumption; Podocytes; Renal Circulation; Signal Transduction; Sirtuin 1; Sodium; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32276962
DOI: 10.1681/ASN.2020010010 -
Hypertension (Dallas, Tex. : 1979) May 2020GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in...
GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in mice. mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.
Topics: Animals; Arteries; Blood Pressure; Bosentan; Endothelin-1; Glomerular Filtration Rate; Heart; Hemodynamics; Infusions, Intravenous; Kidney; Lactates; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Oligopeptides; Paracrine Communication; Peptides, Cyclic; Pericytes; Piperidines; RNA, Messenger; Receptors, G-Protein-Coupled; Renal Circulation; Reperfusion Injury
PubMed: 32200679
DOI: 10.1161/HYPERTENSIONAHA.119.14308