Enhanced β-adrenergic response in mice with dominant-negative expression of the PKD2L1 channel.

Manabu Murakami,Kazuyoshi Hirota,Takayuki Nemoto,Shirou Itagaki,Takayoshi Ohba,Yasushi Matsuzaki,Yujiro Asada,Daisuke Sawamura,Ichiro Miyoshi,Yuichi Toyama,Hirofumi Tomita,Manabu Yonekura,Agnieszka M Murakami,Alexander G Obukhov

doi:10.1371/journal.pone.0261668

Manabu Murakami, Kazuyoshi Hirota + Show 12 more

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https://doi.org/10.1371/journal.pone.0261668

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Abstract

Polycystic kidney disease (PKD) is the most common genetic cause of kidney failure in humans. Among the various PKD-related molecules, PKD2L1 forms cation channels, but its physiological importance is obscure. In the present study, we established a transgenic mouse line by overexpressing the dominant-negative form of the mouse PKD2L1 gene (i.e., lacking the pore-forming domain). The resulting PKD2L1del-Tg mice exhibited supraventricular premature contraction, as well as enhanced sensitivity to β-adrenergic stimulation and unstable R-R intervals in electrocardiography. During spontaneous atrial contraction, PKD2L1del-Tg atria showed enhanced sensitivity to isoproterenol, norepinephrine, and epinephrine. Action potential recording revealed a shortened action potential duration in PKD2L1del-Tg atria in response to isoproterenol. These findings indicated increased adrenergic sensitivity in PKD2L1del-Tg mice, suggesting that PKD2L1 is involved in sympathetic regulation.

Highlights

Polycystic kidney disease (PKD) is a common autosomal dominant Mendelian disorder affecting 0.1% of the population, and it is the most common genetic cause of kidney failure in humans [1]
PKD is a monogenic hereditary disease characterized by multiple, progressive bilateral cystic dilatations of renal tubules, which result in renal failure
The overexpression construct was generated by ligating two PCR-amplified fragments of the PKD2L1 coding sequence into the pQBI plasmid (Wako Chemicals), controlled by the CMV promoter; enhanced green fluorescent protein sequence was followed by the PKD2L1 sequence and a rabbit globin poly(A) signal (Fig 1A)

Summary

Introduction

Polycystic kidney disease (PKD) is a common autosomal dominant Mendelian disorder affecting 0.1% of the population, and it is the most common genetic cause of kidney failure in humans [1]. PKD is a monogenic hereditary disease characterized by multiple, progressive bilateral cystic dilatations of renal tubules, which result in renal failure. Positional cloning analysis has revealed two loci of etiological importance: polycystin-1 (PKD1), mapped to chromosome 16p13.3, and polycystin-2 (PKD2), mapped to chromosome 4q21–23) [2,3,4,5]. Enhanced β-adrenergic response with dominant-negative PKD2L1 expression

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