Name: use of ultra-high field mri in small rodent models of polycystic kidney disease for in vivo phenotyping and drug monitoring
Uploaded: 2015-06-23T14:00:00
Description: Watch this Scientific Journal Video about Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring at JoVE.com

We thank Drs. Xiaofang Wang and Katharina Hopp for their invaluable help with the animal models. This work has been supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK090728, DK058816).

Before starting any procedures with live animals, experimental protocols should be approved by the institutional animal care and use committee (IACUC).
1. Scanner Configuration
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	<li>Before starting, make sure the heater is in OFF position.</li>
	<li>Select the mini imaging gradient and 38 mm RF coil and mini imaging holder.</li>
	<li>In the central bore of the holder install the variable temperature assembly.</li>
</ol>
2. Animal Preparation
<ol>
	<li>For MRI e...

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This manuscript shows the feasibility of using UHF MRI as a tool for in vivo phenotypical characterization or drug monitoring in rodent models for PKD.
We describe experiments done at 16.4 T with a wide bore Avance III high resolution NMR spectrometer equipped with micro and mini imaging accessories. The spectrometer was driven by the acquisition and processing software TopSpin2.0PV controlled by Paravision 5.1 imaging software. Because the rodent size varies in longitudinal studies, ...

Polycystic Kidney Disease (PKD) includes a group of monogenic disorders characterized by the development of renal cysts. Among them are autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-recessive polycystic kidney disease (ARPKD), which represent the most common types1,2. ADPKD, the most frequent form of hereditary renal cystic diseases, is originated by mutations in the PKD1 or PKD2 genes. It is characterized by late-onset, multiple bilateral renal cysts, accompanied by variable extra-renal cysts, as well as cardiovascular and muscle skeletal abnormalities. ARPKD, most commonly affecting newborns and young children, is caused by mutations in PKHD1 and is characterized by enlarged echogenic kidneys and congenital hepatic fibrosis3.
Importantly, ADPKD is characterized by heterogeneity, both at the gene (genic) and mutation (allelic) levels, which results in substantial phenotypic variability. Mutations in the PKD1 gene are associated with severe clinical presentation (numerous cysts, early diagnosis, hypertension, and hematuria), as well as rapid progression to end-stage renal disease (20 years earlier than patients with PKD2 mutations)4. Severe polycystic liver disease (PLD) and vascular abnormalities can be associated with mutations in both PKD1 and PKD25. The majority of renal complications of ADPKD arise mainly as a consequence of the cyst expansion along with associated inflammation and fibrosis. Cyst development starts in utero and continues through the patient lifetime. Kidneys usually maintain their reniform shape even though they could reach more than 20 times the normal kidney volume. Most of the patients present bilateral distribution of renal cysts, but in some unusual cases, cyst may develop in a unilateral or asymmetric pattern.
A major challenge for nephrologists following patients with ADPKD or implementing therapies is the natural history of the disease. During most of its course, the renal function remains normal and by the time the renal function starts to decline, most of the kidneys have been replaced by cysts. When therapies are implemented at later stages, it is less likely to be successful since the patient may already have reached a point of no return in chronic kidney disease. In contrast, when therapies are started at early stages, it is difficult to identify a response based solely on glomerular filtration rate. As a result, the notion of kidney volume as a marker of disease progression gained attention.
The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study has shown that in patients with ADPKD the increase in kidney and cyst volumes directly correlates with renal function deterioration, underscoring the potential of Total Kidney Volume (TKV) as a surrogate marker for disease progression6,7. Consequently, TKV is currently used as primary or secondary endpoint in multiple clinical trials for ADPKD2,8,9.
Multiple murine models including spontaneous mutations and genetically engineered have shed light on the pathogenesis of PKD10,11. Pkd1 or Pkd2 models (mutations in either Pkd1 or Pkd2) have become the most popular ones, as they perfectly mimic human disease. In addition, rodent models with mutations in genes other than Pkd1 or Pkd2 genes have been used as an experimental platform to elucidate signaling pathways related to the disease. In addition, several of these models have been used to test potential therapies. However, a limiting factor in many rodent studies for PKD is often the lack of efficient non-invasive methods to sequentially analyze the anatomical and functional changes in the kidney.
Magnetic resonance imaging (MRI) is the current gold standard imaging technique to follow ADPKD patients, providing excellent soft tissue contrast and anatomic detail, and allowing TKV measurements. Even though MRI is well established for anatomical imaging in larger animals and humans, imaging small rodents in vivo entails additional technical challenges, where the ability to acquire high resolution images may limit its usefulness. With the introduction of Ultra-high field (UHF) MRI (7-16.4 T) and the development of stronger gradients, it is now possible to achieve higher signal-to noise ratios and spatial resolution of MRI images with a diagnostic quality similar to that obtained in humans. Consequently, the use of UHF MRI for in vivo imaging of small rodent models for PKD has become a powerful tool for researchers.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>AVANCEIII-700 (16.4 T)</td>
			<td>Bruker</td>
			<td>BH067206</td>
			<td>Wide-bore two channel multinuclear spectrometer equipped with mini and micro-imaging accessories for in vivo small rodent imaging</td>
		</tr>
		<tr>
			<td>TopSpin2.0PV&#160;</td>
			<td>Bruker</td>
			<td>H9088TA2</td>
			<td>Spectrometer processing software&#160;</td>
		</tr>
		<tr>
			<td>Paravision 5.1&#160;</td>
			<td>Bruker</td>
			<td>T10314L5</td>
			<td>Imaging sofware</td>
		</tr>
		<tr>
			<td>VTU BVT 3000 digital</td>
			<td>Bruker</td>
			<td>W1101095</td>
			<td>Temperature controller</td>
		</tr>
	</tbody>
</table>

use of ultra-high field mri in small rodent models of polycystic kidney disease for in vivo phenotyping and drug monitoring

Several in vivo pre-clinical studies in Polycystic Kidney Disease (PKD) utilize orthologous rodent models to identify and study the genetic and molecular mechanisms responsible for the disease, and are very convenient for rapid drug screening and testing of promising therapies. A limiting factor in these studies is often the lack of efficient non-invasive methods for sequentially analyzing the anatomical and functional changes in the kidney. Magnetic resonance imaging (MRI) is the current gold standard imaging technique to follow autosomal dominant polycystic kidney disease (ADPKD) patients, providing excellent soft tissue contrast and anatomic detail and allowing Total Kidney Volume (TKV) measurements.A major advantage of MRI in rodent models of PKD is the possibility for in vivo imaging allowing for longitudinal studies that use the same animal and therefore reducing the total number of animals required. In this manuscript, we will focus on using Ultra-high field (UHF) MRI to non-invasively acquire in vivo images of rodent models for PKD. The main goal of this work is to introduce the use of MRI as a tool for in vivo phenotypical characterization and drug monitoring in rodent models for PKD.

In this manuscript, we aim to show the usefulness of UHF MRI as a tool for in vivo phenotypical characterization or drug monitoring in rodent models for PKD and other kidney diseases. All of the experiments were part of experimental protocols approved by the IACUC.
In vivo phenotyping of small rodent models for PKD using UHF MRI:
All imaging studies were performed on live animals under isoflurane anesthesia, with a Bruker AVANCEIII-700 (16.4 T) vertic...

Watch this Scientific Journal Video about Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring at JoVE.com

Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring

The use of ultra-high field MRI as a non-invasive way to obtain phenotypic information of rodent models for polycystic kidney disease and to monitor interventions is described. Compared with the traditional histological approach, MRI images can be acquired in vivo, allowing for longitudinal follow-up.

Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring

Several in vivo pre-clinical studies in Polycystic Kidney Disease (PKD) utilize orthologous rodent models to identify and study the genetic and molecular ...

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