Chronic kidney disease (CKD) is characterized by irreversible pathological processes that result in the development of end-stage renal disease (ESRD). Accumulating evidence has emphasized the important role of chronic hypoxia in the tubulointerstitium in the final common pathway that leads to development of ESRD. The causes of chronic hypoxia in the tubulointerstitium are multifactorial and include mechanisms such as hemodynamic changes and disturbed oxygen metabolism of resident kidney cells. Epidemiological studies have revealed an association between CKD and systemically hypoxic conditions, such as chronic obstructive pulmonary disease and sleep apnea syndrome. In addition to tubulointerstitial hypoxia, glomerular hypoxia can occur and is a crucial factor in the development of glomerular disorders. Chemical compounds, polarographic sensors, and radiographical methods can be used to detect hypoxia. Therapeutic approaches that target chronic hypoxia in the kidney should be effective against a broad range of kidney diseases. Amelioration of hypoxia is one mechanism of inhibiting the renin-angiotensin system, the current gold standard of CKD therapy. Future therapeutic approaches include protection of the vascular endothelium and appropriate activation of hypoxia-inducible factor, a key transcription factor involved in adaptive responses against hypoxia.

The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease

The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (QO2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension.


The metabolic efficiency for solute transport (QO2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction.


Sustained hyperglycaemia results in increased kidney QO2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased QO2 is not matched by a similar increase in O2 delivery.


Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function.


Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

/pdf/determinants-of-kidney-oxygen-consumption-and-their-1yuypauz1d.pdf

Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension

Rationale: Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. Objective: To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. Methods and Results: Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II–induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4 + and CD8 + T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II–treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Conclusions: Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.

Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension

Objectives:Recent animal studies with dynamic contrast enhanced magnetic resonance imaging have demonstrated that a separable compartment model provides more accurate assessments of glomerular filtration than the Patlak model. In this study, the feasibility of the separable compartment model for the

MRI-measurement of perfusion and glomerular filtration in the human kidney with a separable compartment model.

Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress

Diabetes mellitus is a leading cause of end-stage renal disease (ESRD). The pathogenesis of diabetic nephropathy is not yet well understood.1 At the onset of diabetes mellitus, the intrarenal hemodynamic abnormalities manifest in the form of glomerular hyperfiltration2 and high oxygen consumption3 and may be the factors that are responsible for the onset and progression of diabetic nephropathy (DN).4 Several mechanisms associated with hypoxia may be involved in the progression of nephropathy in patients with diabetes.5,6

Although the significance of renal hypoxia is well established in ischemic nephropathy, the same is not appreciated in diabetic nephropathy. With molecular markers being identified to be useful in monitoring hypoxia,7 there is new interest in studying renal hypoxia in diabetes.8–10 At least 2 major causes of renal hypoxia are appreciated within diabetic kidneys, one as the result of increased oxygen consumption to support sodium reabsorption during the hyper-filtration stage (functional hypoxia) and the other as the result of oxidative stress (imbalance of vasoactive substances), both of which are relevant to pathophysiology of DN.11 The relative contribution of these 2 mechanisms may be variable over time. It is suspected that functional hypoxia is the dominant factor early in the progression and oxidative stress may become dominant in the later stages.

The maintenance of normal renal blood perfusion and oxygenation is critical in the control of renal function. The oxygen tension (pO2) in the renal medulla is low because of countercurrent oxygen diffusion between descending and ascending vasa recta. In addition, the high rate of ion transport activity in the thick ascending limbs of the loops of Henle also contributes to a low pO2 in the renal medulla. Therefore, the renal medulla is especially susceptible to further decrease in the pO2.12

It has been postulated that hypoxia may ultimately cause glomerular damage, leading to a progressive loss of renal function.13 Furthermore, complete renal ischemia in diabetic rats has been shown to cause accelerated renal injury with lesions similar to those seen in human diabetic nephropathy.14 A recent study has shown that the pO2 in chronic diabetic rats is decreased throughout the renal parenchyma.15 Moreover, the outer medullary cells of diabetic rats have been shown to exhibit a significantly higher consumption of oxygen when compared with cortical cells.15 Hypoxia also has been associated with the development of diabetic nephropathy despite controlled glycemia.6

Measurements of tissue oxygenation have been performed primarily in animal models using microelectrodes, a labor intensive and extremely fragile technique and hence limited to a handful of laboratories around the world. The availability of alternate and more robust technologies could allow for more widespread use of these measurements. Oxy-Lite is a novel laser-based technology that is not as fragile and labor intensive compared with microelectrode measurements. Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has been shown to be very useful in monitoring intrarenal oxygenation.16–32 A major advantage of the noninvasive BOLD MRI is the ability to perform similar measurement in humans.

The primary objective of this study was to demonstrate the feasibility of monitoring early changes in renal oxygenation by BOLD MRI and to correlate them with those measured by novel laser based invasive pO2 and blood flow probes. This is important for proper interpretation of BOLD MRI data because they do not differentiate changes as the result of oxygen supply versus demand. The secondary objective was to determine whether there is any temporal variation in the level of hypoxia during a 4-week period after the administration of STZ.

/pdf/early-changes-with-diabetes-in-renal-medullary-hemodynamics-hm5qjcqsut.pdf

Early changes with diabetes in renal medullary hemodynamics as evaluated by fiberoptic probes and BOLD magnetic resonance imaging.

Purpose

To extend observations on intra-renal oxygenation with blood oxygen level-dependent (BOLD) MRI in human and rats to mouse kidneys imaged with a human whole-body scanner.



Materials and Methods

Renal BOLD MRI studies were performed on a 3.0T scanner using a multiple gradient-echo (mGRE) sequence with a custom-designed 2.0-cm surface coil to acquire six T2*-weighted images in mice (N = 8) at an in-plane resolution of 156 × 156 μm2. BOLD MRI data were obtained before and after administration of furosemide (10 mg/kg intravenously [i.v.]).



Results

The mean weight of eight mice was 24.6 ± 1.0 g. The baseline renal R2* (mean ± standard error [SE]) was 28.6 ± 2.1 seconds–1 in the renal cortex (CO), 35.4 ± 2.2 in the outer medulla (OM), and 21.2 ± 2.1 seconds–1 in the inner medulla (IM). The BOLD response to furosemide (ΔR2*) was 4.1 ± 1.4 in the CO, 10.1 ± 2.1 seconds–1 in the OM, and 3.4 ± 0.8 seconds–1 in the IM in mice.



Conclusion

Intrarenal BOLD MR images with sufficiently high resolution can be obtained on a human whole-body scanner when combined with a small receiver coil to allow studies in mice. Both baseline R2* and ΔR2* values following administration of furosemide were consistent with previous experience in humans and rats. J. Magn. Reson. Imaging 2007. © 2007 Wiley-Liss, Inc.

Evaluation of intrarenal oxygenation in mice by BOLD MRI on a 3.0T human whole-body scanner.

Purpose:

To determine whether MRI in combination with an intravascular contrast agent is sensitive to pharmacologically induced vasodilation and vasoconstriction in the rat kidney.



Materials and Methods:

R2 imaging was performed in 25 Sprague Dawley rats at 3 Tesla in the presence of ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) agent with a long plasma half-life. R2 changes were measured following manipulation of blood volume by intravenous administration of adenosine, a short-acting vasodilator, or NG-nitro-L-arginine methyl ester (L-NAME), a long-acting nitric oxide synthase inhibitor with known vasoconstrictive effects. As a control, R2 responses to adenosine and L-NAME were also examined in the absence of ferumoxytol.



Results:

In the presence of ferumoxytol, adenosine induced a significant increase in R2, while L-NAME produced a reduction, although the latter was not statistically significant. Control experiments revealed small R2 changes in the absence of ferumoxytol. An incidental finding was that the cross-sectional area of the kidney also varied dynamically with adenosine and L-NAME.



Conclusion:

Our results suggest that ferumoxytol-enhanced R2 imaging is sensitive to adenosine-induced vasodilation. The responses to L-NAME, however, were not statistically significant. The variations in kidney size and the R2 changes in the absence of ferumoxytol may reflect alterations in the volume of the renal tubules. J. Magn. Reson. Imaging 2011;33:1091–1099. © 2011 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/jmri.22526

Sensitivity of USPIO‐enhanced R2 imaging to dynamic blood volume changes in the rat kidney

Purpose:

To evaluate intra-renal oxygenation by blood oxygenation level dependent (BOLD) MRI in rat kidneys during water loading and to investigate if the NO donating moiety in naproxcinod could compensate for the effect of cyclooxygenase (COX) inhibition of naproxen.



Materials and Methods:

Nineteen male Sprague Dawley rats were divided into three groups and dosed with vehicle, naproxen or naproxcinod by gavage for two weeks. On the day of the experiment, hypotonic saline with glucose was infused intravenously to induce water diuresis. BOLD MRI data to monitor renal oxygenation and timed urine samples for estimation of prostaglandins (PGs) and urine flow were obtained.



Results:

The data in this study is consistent with previous experience in humans in that pre-treatment with naproxen abolished the improvement in medullary oxygenation during water loading. In addition, the inhibition of PGs by naproxcinod reached similar levels as naproxen but maintained the improvement in oxygenation in renal medulla during water loading.



Conclusion:

This suggests that naproxcinod may have less nephrotoxicity and that the NO donating moiety partially compensates for the hemodynamic effects of prostaglandin inhibition by naproxen. J. Magn. Reson. Imaging 2010;32:383–387. © 2010 Wiley-Liss, Inc.

/pdf/intra-renal-oxygenation-in-rat-kidneys-during-water-loading-2jl0zo6a0z.pdf

Intra-renal oxygenation in rat kidneys during water loading: effects of cyclooxygenase (COX) inhibition and nitric oxide (NO) donation.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Lin Ji

Author Tools

Chat about Author

Papers

Early changes with diabetes in renal medullary hemodynamics as evaluated by fiberoptic probes and BOLD magnetic resonance imaging.

Evaluation of intrarenal oxygenation in mice by BOLD MRI on a 3.0T human whole-body scanner.

Sensitivity of USPIO‐enhanced R2 imaging to dynamic blood volume changes in the rat kidney

Intra-renal oxygenation in rat kidneys during water loading: effects of cyclooxygenase (COX) inhibition and nitric oxide (NO) donation.