Research Article: Deficient Response to Experimentally Induced Alkalosis in Mice with the Inactivated insrr Gene

Date Published: , 2011

Publisher: A.I. Gordeyev

Author(s): I.E. Deyev, D.I. Rzhevsky, A.A. Berchatova, O.V. Serova, N.V. Popova, A.N. Murashev, A.G. Petrenko.

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Abstract

Currently, the molecular mechanisms of the acid-base equilibrium maintenance in
the body remain poorly understood. The development of alkalosis under various
pathological conditions poses an immediate threat to human life. Understanding
the physiological mechanisms of alkalosis compensation may stimulate the
development of new therapeutic approaches and new drugs for treatment. It was
previously shown that the orphan insulin receptor-related receptor (IRR) is
activated by mildly alkaline media. In this study, we analyzed mutant mice with
targeted inactivation of theinsrr gene encoding IRR, and
revealed their phenotype related to disorders of the acid-base equilibrium.
Higher concentrations of bicarbonate and CO2were found in the blood
ofinsrr knockout mice in response to metabolic
alkalosis.

Partial Text

The insulin receptor-related receptor (IRR) is a receptor tyrosine kinase that
belongs to the minifamily of the insulin receptor, which also includes the insulin
receptor and insulin-like growth factor receptor [1]. The cDNA sequence of IRR was cloned in 1989 [2]; however, as of now no natural agonists for IRR possessing a
peptide or protein character have been found [3].

Antibodies and Western-Blot Analysis

In order to obtain a homozygous line of the insrr knockout mice,
animals with the insrr gene, as well as those with the insulin
receptor and insulin-like growth factor receptor genes knocked out (triple
heterozygous knockout [10]), were crossed
with the C57BL6 mice of the wild type. The presence of alleles with the
insrr gene knocked out and the absence of alleles with the
insulin receptor and insulin-like growth factor receptor genes knocked out were
verified by PCR on the genomic DNA of mice ( Fig. 1A ).

It was demonstrated in our previous studies that IRR is a sensor of extracellular
alkaline media. The absence of this gene in the body leads to a disturbance in the
compensation of metabolic alkalosis, induced by feeding animals with alkaline food
for several days. This effect resulted from a defect in bicarbonate secretion by the
kidneys of the insrr knockout mice [8]. The results obtained in studying the compensation of induced
alkalosis under acute conditions (5–15 min) confirm our hypothesis on the
compensatory role of IRR in the secretion of bicarbonate. It can be concluded that
IRR-dependent compensation of alkalosis proceeds rather fast. It is important to
note that, in mice with IRR knocked out, compensation of alkalosis is also observed
(since the blood pH value decreases). However, this occurs not due to the secretion
of excess amounts of bicarbonate, but as a result of the increase in the
concentration of CO 2 in the blood; the latter most likely results from
the decelerated breathing or accelerated metabolism. Thus, it can be concluded that
IRR plays a significant role in the physiological mechanisms of regulation of the
acid-base equilibrium and that mice with IRR knocked out can be used as animal
models to study pathological development of metabolic alkalosis.

 

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