Renal blood flow and oxygenation drive nephron progenitor differentiation

During kidney development, the vasculature develops via both angiogenesis (branching from major vessels) and vasculogenesis (de novo vessel formation). The formation and perfusion of renal blood vessels are vastly understudied. In the present study, we investigated the regulatory role of renal blood flow and O2 concentration on nephron progenitor differentiation during ontogeny. To elucidate the presence of blood flow, ultrasound-guided intracardiac microinjection was performed, and FITC-tagged tomato lectin was perfused through the embryo. Kidneys were costained for the vasculature, ureteric epithelium, nephron progenitors, and nephron structures. We also analyzed nephron differentiation in normoxia compared with hypoxia. At embryonic day 13.5 (E13.5), the major vascular branches were perfused; however, smaller-caliber peripheral vessels remained unperfused. By E15.5, peripheral vessels started to be perfused as well as glomeruli. While the interior kidney vessels were perfused, the peripheral vessels (nephrogenic zone) remained unperfused. Directly adjacent and internal to the nephrogenic zone, we found differentiated nephron structures surrounded and infiltrated by perfused vessels. Furthermore, we determined that at low O2 concentration, little nephron progenitor differentiation was observed; at higher O2 concentrations, more differentiation of the nephron progenitors was induced. The formation of the developing renal vessels occurs before the onset of blood flow. Furthermore, renal blood flow and oxygenation are critical for nephron progenitor differentiation.

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Angiotensin 1-7 Administration Increases Renal Blood Flow in the Absence of Bradykinin B2 Receptor in Ovariectomized Estradiol Treated Rats: The Role of Mas Receptor

ACTA MEDICA IRANICA ◽

10.18502/acta.v57i2.1764 ◽

2019 ◽

Author(s):

Shadan Saberi ◽

Aghdas Dehghani ◽

Mehdi Nematbakhsh

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Ovariectomized Rats ◽

Vehicle Group ◽

Estradiol Valerate ◽

Bradykinin B2 Receptor ◽

Hoe 140 ◽

Group 2 ◽

Renal Vascular

Abstract- Renin angiotensin (RAS), kallikrein kinin (KKS), and sex hormonal systems demonstrate a complex contribution in kidney circulation. This study was designed to investigate the role of angiotensin 1-7 (Ang 1-7) receptor (MasR) and of bradykinin B2 receptor (B2R) in renal blood flow (RBF) response to Ang 1-7 infusion in ovariectomized estradiol treated rats. The ovariectomized rats received intramuscular vehicle (group 1, OV) or estradiol valerate (500 µg/Kg/week) (group 2, OVE) for two weeks. Then each group was divided into two subgroups subjected to receive B2R antagonist (HOE-140, subgroup A), or MasR antagonist (A779) plus HOE-140 (subgroup B). RBF and renal vascular resistance (RVR) responses to graded Ang 1-7 infusion were determined. In condition of B2R alone blocking, RBF response to Ang 1-7 in OVE group was significantly greater than that of OV group (P=0.05), however this response difference was failed by co-blockades of MasR and B2R. Estradiol could promote RBF response to graded Ang 1-7 infusion in the absence of B2R alone, however when both receptors (MasR and B2R) were blocked the role of estradiol was limited.

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The role of NOS2 and NOS3 in renal protein and arginine metabolism during early endotoxemia in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00308.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. F816-F822 ◽

Cited By ~ 6

Author(s):

Yvette C. Luiking ◽

Marcella M. Hallemeesch ◽

Wouter H. Lamers ◽

Nicolaas E. P. Deutz

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Protein Turnover ◽

De Novo ◽

Whole Body ◽

Wild Type ◽

Protein Amino Acid ◽

Renal Metabolism ◽

Lps Challenge ◽

Baseline Conditions

Previously, we observed an enhanced renal protein synthesis and increased de novo arginine production in the early response to endotoxemia in wild-type Swiss mice (Hallemeesch MM, Soeters PB, and Deutz NE. Am J Physiol Renal Physiol 282: F316–F323, 2002). To establish whether these changes are regulated by nitric oxide (NO) synthesized by NO synthase isoforms NOS2 and NOS3, we studied C57BL6/J wild-type (WT), NOS2-deficient (NOS2−/−), and NOS3-deficient (NOS3−/−) mice under baseline (unstimulated) and LPS-treated conditions. The metabolism of renal protein, amino acid, and arginine was studied at the whole body level and across the kidney by infusing the stable isotopes l-[phenyl-2H5]phenylalanine, l-[phenyl-2H2]tyrosine, l- guanidino-[15N2]arginine, and l-[ ureido-13C,2H2]citrulline. Renal blood flow was measured using radioactive PAH extraction. Under baseline conditions, renal blood flow was significantly reduced in NOS2−/− mice (0.29 ± 0.01 vs. 0.48 ± 0.07 ml·10 g body wt−1·min−1 in WT) ( P < 0.05), and de novo arginine production was lower in NOS2−/− mice. After LPS challenge, renal protein turnover and arginine production increased in all three groups ( P < 0.05), even though renal de novo arginine synthesis did not increase. The expected increase in renal citrulline production and disposal after LPS was not observed in NOS2−/− mice ( P = 0.06). Collectively, these data show that NOS2 is constitutively expressed in the kidney and remarkably functional as it affects renal blood flow and de novo arginine production under baseline conditions and is important for the increase in renal citrulline turnover during endotoxemia. NOS3, in contrast, appears less important for renal metabolism. The increase in renal protein turnover during endotoxemia does not depend on NOS2 or NOS3 activity.

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Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

Scientific Reports ◽

10.1038/s41598-021-00489-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aleksandra Cwiek ◽

Masako Suzuki ◽

Kimberly deRonde ◽

Mark Conaway ◽

Kevin M. Bennett ◽

...

Keyword(s):

Preterm Birth ◽

Progenitor Cells ◽

Kidney Development ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Neonatal Morbidity ◽

Expression Of Genes ◽

Nephron Progenitor ◽

Lower Expression ◽

Nephrogenic Zone

AbstractPreterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.

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Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽

10.1161/hyp.68.suppl_1.062 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Sumit R Monu ◽

Mani Maheshwari ◽

Hong Wang ◽

Ed Peterson ◽

Oscar Carretero

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Afferent Arteriole ◽

Connecting Tubule ◽

Single Nephron ◽

Renal Micropuncture ◽

The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

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THE ROLE OF INCREASED SYMPATHETIC NERVOUS ACTIVITY FOR THE REDUCED RENAL BLOOD FLOW IN PATIENTS WITH CIRRHOSIS

Clinical Physiology ◽

10.1111/j.1475-097x.1981.tb00941.x ◽

1981 ◽

Vol 1 (s1) ◽

pp. 71-75 ◽

Cited By ~ 1

Author(s):

Helmer Ring-Larsen ◽

Jens H. Henriksen ◽

Birger Hesse ◽

Niels Juel Christensen

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Nervous Activity ◽

Sympathetic Nervous Activity ◽

Sympathetic Nervous

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Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat

AJP Renal Physiology ◽

10.1152/ajprenal.0078.2001 ◽

2001 ◽

Vol 281 (6) ◽

pp. F1132-F1140 ◽

Cited By ~ 19

Author(s):

R. Kramp ◽

P. Fourmanoir ◽

N. Caron

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Receptor Subtypes ◽

Receptor Blockade ◽

Flow Probe ◽

Relative Contribution ◽

No Inhibition ◽

Electromagnetic Flow Probe ◽

Bq 610

First published August 15, 2001; 10.1152/ajprenal.00078.2001.—Renal blood flow (RBF) autoregulatory efficiency may be enhanced during NO inhibition in the rat, as recently reported. Under these conditions, endothelin (ET) synthesis and release may be increased. Our purpose was therefore to determine the role of ET in RBF autoregulatory changes induced by NO inhibition. To address this point, ETA/B receptors were blocked in anesthetized rats with bosentan, or selectively with BQ-610 or BQ-788. NO synthesis was inhibited with N G-nitro-l-arginine methyl ester (l-NAME). Mean arterial pressure (MAP) was decreased after bosentan (−10 mmHg; P < 0.01) or increased after l-NAME (25 mmHg; P < 0.001). RBF measured with an electromagnetic flow probe was reduced byl-NAME (−50%) and by BQ-788 (−24%). The pressure limits of the autoregulatory plateau (PA ∼100 mmHg) and of no RBF autoregulation (Po ∼80 mmHg) were significantly lowered by 15 mmHg after l-NAME but were unchanged after bosentan, BQ-610, or BQ-788. During NO inhibition, autoregulatory resetting was completely hindered by bosentan (PA ∼100 mmHg) and by ETB receptor blockade with BQ-788 (PA ∼106 mmHg), but not by ETA receptor blockade with BQ-610 (PA ∼85 mmHg). These results suggest that the involvement of ET in the RBF autoregulatory resetting occurs during NO inhibition, possibly by preferential activation of the ETB receptor. However, the relative contribution of ET receptor subtypes remains to be further specified.

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Von Hippel-Lindau Acts as a Metabolic Switch Controlling Nephron Progenitor Differentiation

Journal of the American Society of Nephrology ◽

10.1681/asn.2018111170 ◽

2019 ◽

Vol 30 (7) ◽

pp. 1192-1205 ◽

Cited By ~ 3

Author(s):

Kasey Cargill ◽

Shelby L. Hemker ◽

Andrew Clugston ◽

Anjana Murali ◽

Elina Mukherjee ◽

...

Keyword(s):

Mitochondrial Respiration ◽

Metabolic Regulation ◽

Kidney Development ◽

Developmentally Delayed ◽

Metabolic Switch ◽

Von Hippel Lindau ◽

Conditional Deletion ◽

Nephron Progenitors ◽

Ubiquitin Ligase Complex ◽

Nephron Progenitor

BackgroundNephron progenitors, the cell population that give rise to the functional unit of the kidney, are metabolically active and self-renew under glycolytic conditions. A switch from glycolysis to mitochondrial respiration drives these cells toward differentiation, but the mechanisms that control this switch are poorly defined. Studies have demonstrated that kidney formation is highly dependent on oxygen concentration, which is largely regulated by von Hippel-Lindau (VHL; a protein component of a ubiquitin ligase complex) and hypoxia-inducible factors (a family of transcription factors activated by hypoxia).MethodsTo explore VHL as a regulator defining nephron progenitor self-renewal versus differentiation, we bred Six2-TGCtg mice with VHLlox/lox mice to generate mice with a conditional deletion of VHL from Six2+ nephron progenitors. We used histologic, immunofluorescence, RNA sequencing, and metabolic assays to characterize kidneys from these mice and controls during development and up to postnatal day 21.ResultsBy embryonic day 15.5, kidneys of nephron progenitor cell–specific VHL knockout mice begin to exhibit reduced maturation of nephron progenitors. Compared with controls, VHL knockout kidneys are smaller and developmentally delayed by postnatal day 1, and have about half the number of glomeruli at postnatal day 21. VHL knockout nephron progenitors also exhibit persistent Six2 and Wt1 expression, as well as decreased mitochondrial respiration and prolonged reliance on glycolysis.ConclusionsOur findings identify a novel role for VHL in mediating nephron progenitor differentiation through metabolic regulation, and suggest that VHL is required for normal kidney development.

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Quantification of conversion and degradation of circulating angiotensin in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.277.2.r412 ◽

1999 ◽

Vol 277 (2) ◽

pp. R412-R418 ◽

Cited By ~ 1

Author(s):

Johannes Bauer ◽

Heike Berthold ◽

Franz Schaefer ◽

Heimo Ehmke ◽

Niranjan Parekh

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Systemic Circulation ◽

Left Renal Artery ◽

Minor Importance ◽

Ang Ii ◽

Renal Circulation ◽

Degradation Rates ◽

Measured Change

The aim of the present study was to quantify with a uniform technique the rates of conversion of ANG I to ANG II in the lung and kidney and the degradation of both peptides to biologically inactive products in the pulmonary, renal, and systemic circulation. We infused the peptides intravenously, into the left ventricle, and into the left renal artery of rats and compared their effects on renal blood flow. The measured change in renal blood flow was used as a bioassay parameter to estimate the concentration of circulating ANG II. Mathematical analysis of our data allowed us to calculate conversion and degradation rates. Furthermore, the role of aminopeptidases A (EC 3.4.11.7 ) and N (EC 3.4.11.2 ) in the degradation of the peptides in the kidney was investigated by intrarenal infusion of the inhibitor amastatin. Our results show that the conversion rate of ANG I is 75% in the pulmonary and 21% in the renal circulation. Both peptides are degraded by 5% in the pulmonary, by 67% in the systemic, and by 93% in the renal circulation. Amastatin prevented 60% of the renal degradation of the peptides to inactive products, and this effect could be attributed to inhibition of aminopeptidase N. The results indicate that the converting capacity of the kidney is of minor importance for endocrine generation of ANG II but could be useful for the paracrine production.

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Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats

Advances in Pharmacological Sciences ◽

10.1155/2015/801053 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Aghdas Dehghani ◽

Shadan Saberi ◽

Mehdi Nematbakhsh

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Wistar Rats ◽

Group Versus ◽

Dependent Manner ◽

Mas Receptor ◽

Flow Response ◽

Renal Vascular ◽

Dose Dependent

Background. The accompanied role of Mas receptor (MasR), bradykinin (BK), and female sex hormone on renal blood flow (RBF) response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779) and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats.Methods. Ovariectomized Wistar rats received estradiol (OVE) or vehicle (OV) for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP), RBF, and renal vascular resistance (RVR) responses to Ang 1-7 (0, 100, and 300 ng kg−1 min−1) were determined.Results. Percentage change of RBF (%RBF) in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P<0.05). Infusion of 300 ng kg−1 min−1Ang 1-7 increased RBF by6.9±1.9% in OVE group versus0.9±1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly.Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats.

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