Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption

Abstract

Background

The most profound effect of vasopressin on the kidney is to increase water reabsorption through V₂-receptor (V₂R) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of V₂R stimulation on kidney function, isolated from systemic effects.

Methods

The role of V₂R in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula.

Results

Kidneys subjected to V₂R stimulation using desmopressin (DDAVP) displayed stable osmolality and calcium reabsorption throughout the experiment, whereas kidneys not administered DDAVP exhibited a simultaneous fall in urine osmolality and calcium reabsorption. Epithelial sodium channel (ENaC) inhibition using amiloride resulted in a marked increase in potassium reabsorption along with decreased sodium reabsorption.

Conclusions

A stable isolated perfused kidney model with computer-controlled pressure regulation was developed, which retained key physiological functions. The preparation responds to pharmacological inhibition of ENaC channels and activation of V₂R. Using the model, the dynamic effects of V₂R stimulation on calcium handling and urine osmolality could be visualised. The study thereby provides evidence for a stimulatory role of V₂R in renal calcium reabsorption.

Keywords:

• AVP
• ENaC
• kidney
• vasopressin

Disclosure statement

K.B., L.W.O., U.J. and J.H.G. are employed by AstraZeneca. J.S. is employed at the Swedish Medical Products Agency, SE-751 03 Uppsala, Sweden. The views expressed in this paper are the personal views of the author and not necessarily the views of the Government agency.

Additional information

Funding

The experimental study was performed 2013–2014 and was supported by AstraZeneca, Sweden. No financial support has been received from AstraZeneca for preparation of the manuscript.

Notes on contributors

Krister Bamberg

Krister Bamberg, PhD, director, scientific lead, CKD late stage portfolio at Department of Translational Sciences and Experimental Medicine, Early Cardiovascular Renal and Metabolism BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg.

Lena William-Olsson

Lena William-Olsson, BSc, in vivo biologist at Department of Bioscience Renal, Early Cardiovascular Renal and Metabolism BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg.

Ulrika Johansson

Ulrika Johansson, BSc, senior researcher at Department of Bioscience Renal, Early Cardiovascular Renal and Metabolism BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg.

Anders Arner

Anders Arner, MD, PhD, researcher at the Department of Clinical Sciences Lund, Lund University and professor emeritus at the Department of Physiology and Pharmacology, Karolinska Institutet.

Judith Hartleib-Geschwindner

Judith Hartleib-Geschwindner, PhD, senior director and global project lead at Department of Projects, Early Cardiovascular Renal and Metabolism BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg.

Johan Sällström

Johan Sällström, PhD, researcher at the Department of Medical Cell Biology, Uppsala University and clinical assessor at the Swedish Medical Products Agency.