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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 -
BMC Nephrology Feb 2019Magnesium lithospermate B (MLB) can promote renal microcirculation. The aim of the current project was to study whether MLB improves renal hemodynamics, oxygen...
BACKGROUND
Magnesium lithospermate B (MLB) can promote renal microcirculation. The aim of the current project was to study whether MLB improves renal hemodynamics, oxygen consumption and subsequently attenuates hypoxia in rats induced by 5/6th renal Ablation/Infarction(A/I).
METHODS
Chronic renal failure (CRF) was induced in male SD rats by the 5/6 (A/I) surgery. 30 rats were randomly divided into three groups: sham group, 5/6 (A/I) + vehicle group (CRF group) and 5/6 (A/I) + MLB (CRF + MLB) group. 28 days after the surgery, rats were given with saline or 100 mg/kg MLB by i.p. injection for 8 weeks. The 24-h urinary protein (24hUp), serum creatinine (Scr), blood urine nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. The protein expression of Fibronectin (FN), Collagen-I (Col-I), Connective Tissue Growth Factor(CTGF) and Interleukin-6 (IL-6) were measured by Western blot. Renal blood flow (RBF) and renal O consumption (QO) indicated as sodium reabsorption (QO/TNa) were detected before sacrifice. Renal hypoxia was assessed by measuring the protein expression of nNOS, HIF-1α and VEGF.
RESULTS
MLB significantly reduced 24hUp, Scr, BUN, SBP and DBP levels in rats with CRF. The expression of FN, Col-I, CTGF and IL-6 were down-regulated by MLB treatment in rats with CRF. In comparison to sham operated rats, 5/6 (A/I) rats had significantly lower RBF, and MLB significantly increased RBF in rats with CRF. Moreover, QO/TNa was higher in the CRF group as compared to that in the sham group, and it was significantly attenuated in the CRF + MLB group. MLB reversed the expression of nNOS (neuronal nitric oxide synthase), HIF-1α (hypoxia inducible factor-1) and VEGF in rats with CRF.
CONCLUSIONS
MLB improves renal function, fibrosis and inflammation in CRF rats induced by 5/6 (A/I), which is probably related to the increase in RBF, reduction of oxygen consumption and attenuation of renal hypoxia in the remnant kidney with CRF.
Topics: Animals; Cell Hypoxia; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Hemodynamics; Infarction; Kidney; Kidney Function Tests; Ligation; Male; Microcirculation; Nephrectomy; Oxygen Consumption; Phytotherapy; Random Allocation; Rats; Rats, Sprague-Dawley; Renal Artery; Renal Circulation
PubMed: 30755161
DOI: 10.1186/s12882-019-1221-5 -
Journal of the American Heart... Feb 2023Background GLP-1 (glucagon-like peptide-1) receptor agonists exert beneficial long-term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect... (Randomized Controlled Trial)
Randomized Controlled Trial
Background GLP-1 (glucagon-like peptide-1) receptor agonists exert beneficial long-term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is accompanied by suppression of angiotensin II, and is independent of changes in renal plasma flow. In rodents, angiotensin II constricts vasa recta and lowers medullary perfusion. The current randomized, controlled, crossover study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans. Methods and Results Healthy male participants (n=10, aged 27±4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg per minute) or placebo together with infusion of 0.9% NaCl (750 mL/h). Interleaved measurements of renal arterial blood flow, oxygenation (R*), and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. GLP-1 infusion increased medullary perfusion (32±7%, <0.001) and cortical perfusion (13±4%, <0.001) compared with placebo. Here, NaCl infusion decreased medullary perfusion (-5±2%, =0.007), whereas cortical perfusion remained unchanged. R* values increased by 3±2% (=0.025) in the medulla and 4±1% (=0.008) in the cortex during placebo, indicative of decreased oxygenation, but remained unchanged during GLP-1. Blood flow in the renal artery was not altered significantly by either intervention. Conclusions GLP-1 increases predominantly medullary but also cortical perfusion in the healthy human kidney and maintains renal oxygenation during NaCl loading. In perspective, suppression of angiotensin II by GLP-1 may account for the increase in regional perfusion. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04337268.
Topics: Humans; Male; Angiotensin II; Cross-Over Studies; Glucagon-Like Peptide 1; Kidney; Kidney Medulla; Perfusion; Renal Circulation; Sodium Chloride; Young Adult; Adult
PubMed: 36734354
DOI: 10.1161/JAHA.122.027712 -
Pediatric Nephrology (Berlin, Germany) May 2016The longstanding focus in chronic kidney disease (CKD) research has been on the glomerulus, which is sensible because this is where glomerular filtration occurs, and a... (Review)
Review
The longstanding focus in chronic kidney disease (CKD) research has been on the glomerulus, which is sensible because this is where glomerular filtration occurs, and a large proportion of progressive CKD is associated with significant glomerular pathology. However, it has been known for decades that tubular atrophy is also a hallmark of CKD and that it is superior to glomerular pathology as a predictor of glomerular filtration rate decline in CKD. Nevertheless, there are vastly fewer studies that investigate the causes of tubular atrophy, and fewer still that identify potential therapeutic targets. The purpose of this review is to discuss plausible mechanisms of tubular atrophy, including tubular epithelial cell apoptosis, cell senescence, peritubular capillary rarefaction and downstream tubule ischemia, oxidative stress, atubular glomeruli, epithelial-to-mesenchymal transition, interstitial inflammation, lipotoxicity and Na(+)/H(+) exchanger-1 inactivation. Once a a better understanding of tubular atrophy (and interstitial fibrosis) pathophysiology has been obtained, it might then be possible to consider tandem glomerular and tubular therapeutic strategies, in a manner similar to cancer chemotherapy regimens, which employ multiple drugs to simultaneously target different mechanistic pathways.
Topics: Animals; Atrophy; Disease Models, Animal; Disease Progression; Epithelial Cells; Fibrosis; Humans; Kidney Tubules; Renal Circulation; Renal Insufficiency, Chronic; Signal Transduction
PubMed: 26208584
DOI: 10.1007/s00467-015-3169-4 -
Kidney360 May 2024The mechanism of decreased renal function in autosomal dominant polycystic kidney disease has not been elucidated yet. The presented data highlight specific renal...
KEY POINTS
The mechanism of decreased renal function in autosomal dominant polycystic kidney disease has not been elucidated yet. The presented data highlight specific renal hemodynamic changes that occur in patients with autosomal dominant polycystic kidney disease.
BACKGROUND
Although the mechanisms underlying cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) are becoming clearer, those of renal dysfunction are not fully understood. In particular, total kidney volume and renal function do not always correspond. To elucidate this discrepancy, we studied in detail glomerular hemodynamic changes during ADPKD progression.
METHODS
Sixty-one patients with ADPKD with baseline height-adjusted total kidney volume (Ht-TKV) of 933±537 ml/m and serum creatinine of 1.16±0.62 mg/dl were followed for 2 years. GFR and renal plasma flow (RPF) slopes were calculated from inulin clearance (C) and para-aminohippuric acid clearance (C), respectively, while glomerular hydrostatic pressure (P), afferent resistance (R), and efferent resistance (R) were estimated using the Gomez formulas. Each parameter was compared with baseline Ht-TKV. Patients were also subclassified into 1A–1B and 1C–1E groups according to the baseline Mayo imaging classification and then compared with respect to GFR, RPF, filtration fraction, and glomerular hemodynamics.
RESULTS
After 2 years, Ht-TKV increased (933±537 to 1000±648 ml/m, < 0.01), GFR decreased (66.7±30 to 57.3±30.1 ml/min per 1.73 m, < 0.001), and RPF decreased (390±215 to 339±190 ml/min per 1.73 m, < 0.05). Furthermore, P was decreased and R was increased. Baseline Ht-TKV was inversely correlated with GFR (=−0.29, < 0.05), but there was no association between baseline Ht-TKV and RPF, P, R, or R annual changes. However, despite an increase in R in the 1A–1B group, R was decreased in the 1C–1E group. As a result, R slope was significantly lower in the 1C–1E group than the 1A–1B group over time (−83 [−309 to 102] to 164 [−34 to 343] dyne·s·cm, < 0.01).
CONCLUSIONS
This is the first report examining yearly changes of GFR (inulin), RPF (para-aminohippuric), and renal microcirculation parameters in patients with ADPKD. Our results demonstrate that GFR reduction was caused by R increase, which was faster because of R decrease in patients with faster Ht-TKV increase.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Kidney; Hemodynamics; Adult; Male; Female; Glomerular Filtration Rate; Renal Circulation; Middle Aged
PubMed: 38511865
DOI: 10.34067/KID.0000000000000412 -
American Journal of Physiology.... Nov 2018Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response...
Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels ( P < 0.0001) and renal arterial blood flow ( P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS ( P = 0.026). Pretreatment with endothelin receptor type A (ET) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats ( P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ET and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats ( P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ET upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS. NEW & NOTEWORTHY Hepatorenal syndrome (HRS) occurred in advanced cirrhosis after large-volume paracentesis or bacterial peritonitis. We demonstrated that intraperitoneal lipopolysaccharide (LPS) enhanced renal vascular reactivity to endothelin-1 (ET-1) in cirrhotic rats, accompanied by inducible nitric oxide synthase inhibition, endothelin receptor type A (ET) upregulation, and subsequent extracellular signal-regulated kinase activation in renal medulla. Pretreatment with ET antagonist abrogated the LPS-enhanced renal vascular response in common bile duct ligation rats. These findings suggest that further clinical investigation of ET-1-targeted therapy may be feasible in the control of HRS.
Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Endotoxemia; Hepatorenal Syndrome; Lipopolysaccharides; MAP Kinase Signaling System; Male; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Circulation; Vasodilation
PubMed: 30095297
DOI: 10.1152/ajpgi.00302.2017 -
Experimental Physiology Jul 2018What is the central question of this study? We hypothesized that chronic mitoprotection would decrease renal vascular remodelling and dysfunction in swine metabolic...
NEW FINDINGS
What is the central question of this study? We hypothesized that chronic mitoprotection would decrease renal vascular remodelling and dysfunction in swine metabolic syndrome. What is the main finding and its importance? This study shows that experimental metabolic syndrome exerts renal microvascular and endothelial cell mitochondrial injury, which were attenuated by mitoprotection, underscoring the contribution of mitochondrial injury to the pathogenesis of metabolic syndrome-induced vascular damage.
ABSTRACT
The metabolic syndrome (MetS) induces intrarenal microvascular disease, which may involve mitochondrial injury. The mitochondrial cardiolipin-targeting peptide elamipretide (ELAM) improves the microcirculation in post-stenotic kidneys, but its ability to attenuate MetS-induced renal vascular damage is unknown. We hypothesized that chronic treatment with ELAM would decrease renal vascular remodelling and function in swine MetS. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with daily injections of ELAM (0.1 mg kg ), and lean control (Lean) animals (n = 6 each). Single-kidney regional perfusion, blood flow and glomerular filtration rate were measured with multi-detector computed tomography (CT). Peritubular capillary (PTC) endothelial cell (EC) mitochondrial density and cardiolipin content were assessed in situ, as were PTC-EC apoptosis and oxidative stress. The spatial density of PTCs (Haematoxylin and Eosin staining) and renal microvessels (micro-CT), and renal artery endothelial function (organ bath) were characterized. Regional perfusion and serum creatinine were preserved in MetS pigs, but renal blood flow and glomerular filtration rate were higher compared with Lean. Mitochondrial density and cardiolipin content were diminished in MetS PTC-ECs, but improved in ELAM-treated pigs, as did PTC density. Elamipretide also attenuated PTC-EC oxidative stress and apoptosis. Furthermore, ELAM improved renal microvascular density, decreased microvascular remodelling and restored endothelial nitric oxide expression and endothelium-dependent relaxation of renal artery segments. In conclusion, MetS-induced mitochondrial alterations might contribute to renal PTC and microvascular loss and might impair renal artery endothelial function in pigs. Mitoprotection with ELAM preserved a hierarchy of renal vessels, underscoring its potential to ameliorate renal vascular injury in MetS.
Topics: Animals; Antioxidants; Apoptosis; Endothelial Cells; Female; Glomerular Filtration Rate; Kidney; Metabolic Syndrome; Mitochondria; Oligopeptides; Oxidative Stress; Renal Circulation; Swine
PubMed: 29714040
DOI: 10.1113/EP086988 -
Kidney International Aug 2017The global burden of kidney disease is increasing strikingly in parallel with increases in obesity and diabetes. Indeed, chronic kidney disease (CKD) and end-stage renal... (Review)
Review
The global burden of kidney disease is increasing strikingly in parallel with increases in obesity and diabetes. Indeed, chronic kidney disease (CKD) and end-stage renal disease (ESRD) coupled with comorbidities such as obesity, diabetes, and hypertension cost the health care system hundreds of billions of dollars in the US alone. The progression to ESRD in patients with obesity and diabetes continues despite widespread use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) along with aggressive blood pressure and glycemic control in these high-risk populations. Thereby, it is increasingly important to better understand the underlying mechanisms involved in obesity-related CKD in order to develop new strategies that prevent or interrupt the progression of this costly disease. In this context, a key mechanism that drives development and progression of kidney disease in obesity is endothelial dysfunction and associated tubulointerstitial fibrosis. However, the precise interactive mechanisms in the development of aortic and kidney endothelial dysfunction and tubulointerstitial fibrosis remain unclear. Further, strategies specifically targeting kidney fibrosis have yielded inconclusive benefits in human studies. While clinical data support the benefits derived from inhibition of the RAAS, there is a tremendous amount of residual risk for the progression of kidney disease in individuals with obesity and diabetes. There is promising experimental data to suggest that exercise, targeting inflammation and oxidative stress, lowering uric acid, and targeting the mineralocorticoid receptor signaling and/or sodium channel inhibition could improve tubulointerstitial fibrosis and mitigate progression of kidney disease in persons with obesity and diabetes.
Topics: Aldosterone; Animals; Humans; Insulin Resistance; Kidney; Kidney Failure, Chronic; Obesity; Receptors, Mineralocorticoid; Renal Circulation; Renin-Angiotensin System
PubMed: 28341271
DOI: 10.1016/j.kint.2016.12.034 -
American Journal of Physiology.... Feb 2020Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass... (Comparative Study)
Comparative Study
Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep ( = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL·kg·min and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference ± SD from conscious state: -16 ± 14%). However, during CPB renal blood flow was reduced (-55 ± 13%) and renal medullary tissue became hypoxic (-20 ± 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.
Topics: Acute Kidney Injury; Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Biomarkers; Cardiopulmonary Bypass; Fentanyl; Hemodynamics; Hypoxia; Kidney Medulla; Models, Animal; Oxygen; Propofol; Protective Factors; Renal Circulation; Risk Factors; Sheep, Domestic; Time Factors
PubMed: 31823674
DOI: 10.1152/ajpregu.00290.2019 -
American Journal of Nephrology 2020Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial...
BACKGROUND
Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery.
METHODS
Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR).
RESULTS
Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment.
CONCLUSIONS
Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.
Topics: Animals; Atherosclerosis; Disease Models, Animal; Elastin; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Microvessels; Peptides; Recombinant Fusion Proteins; Recovery of Function; Renal Artery Obstruction; Renal Circulation; Sus scrofa; Vascular Endothelial Growth Factor A
PubMed: 33130676
DOI: 10.1159/000511260