Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice

Lichao Chen; Akemi Gunji; Akiko Uemura; Hisako Fujihara; Kentaro Nakamoto; Takae Onodera; Yuka Sasaki; Shoji Imamichi; Mayu Isumi; Tadashige Nozaki; Nobuo Kamada; Kou-Ichi Jishage; Mitsuko Masutani

doi:10.1016/j.bcp.2019.07.003

Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice

Biochem Pharmacol. 2019 Sep:167:116-124. doi: 10.1016/j.bcp.2019.07.003. Epub 2019 Jul 19.

Authors

Affiliations

¹ Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
² Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Oral Surgery, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo, Japan.
³ Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁴ Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Oral and Maxillo-facial Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁶ Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
⁷ Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Pharmacology, Faculty of Dentistry, Osaka Dental University, 8-1, Kuzuhahanazono-cho, Hirakata, Osaka 573-1121, Japan.
⁸ Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
⁹ Chugai Research Institute for Medical Science, Inc., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
¹⁰ Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: mmasutan@nagasaki-u.ac.jp.

PMID: 31326434
DOI: 10.1016/j.bcp.2019.07.003

Abstract

Poly(ADP-ribose) glycohydrolase (Parg) is a central enzyme for poly(ADP-ribose) degradation. We established a Parg^+/- mice strain by deletion of a part of exon 1 and around 0.4-kb upstream of sequences of the Parg gene. Parg^-/- embryos obtained by intercrossing the Parg^+/- mice died in utero between 4.5 and 9.5 days postcoitum. We examined whether poly(ADP-ribose) polymerase-1 (Parp-1) deficiency could rescue embryonic lethality of Parg^-/- mice. Parg^-/-Parp-1^-/- mice were born viable at a reduced frequency from the expected mendelian ratio in the intercross progeny of Parg^+/-Parp-1^-/- mice. The results suggest a possibility that the presence of Parp-1 is responsible for the lethality of Parg^-/- embryos, and Parg molecules or Parg activity degrading poly(ADP-ribose) might be important for embryogenesis. In Parg^-/-Parp-1^-/- mice, Parg protein was not detected in various tissues, and the protein level of Timm23, a 5'-upstream gene of Parg, was reduced compared with that in Parg^+/+Parp-1^-/- mice. Parg^-/-Parp-1^-/- mice showed retarded growth compared with Parg^+/+Parp-1^-/- mice, and died within 3 months of age accompanied with severe renal failure. Glomerular sclerosis, tubular dilatation, and hyaline casts in the kidney were observed in Parg^-/-Parp-1^-/- mice. An increase in blood urea nitrogen (p < 0.05), a marked increase of albumin level in urine (p < 0.01) and its concomitant decrease in serum (p < 0.05) were also detected in Parg^-/-Parp-1^-/- mice compared with the Parg^+/+Parp-1^-/- counterpart. The results imply that the combined Parg and Parp-1 loss with a hypomorphic state of Timm23 leads to the development of severe renal failure.

Keywords: Parg; Parp-1; Poly(ADP-ribose); Renal failure; Timm23.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Coculture Techniques
Glycoside Hydrolases / deficiency*
Glycoside Hydrolases / genetics
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Mitochondrial Membrane Transport Proteins / deficiency*
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Precursor Protein Import Complex Proteins
Poly (ADP-Ribose) Polymerase-1 / deficiency*
Poly (ADP-Ribose) Polymerase-1 / genetics
Renal Insufficiency / genetics
Renal Insufficiency / metabolism*
Renal Insufficiency / pathology*

Substances

Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
Timm23 protein, mouse
Parp1 protein, mouse
Poly (ADP-Ribose) Polymerase-1
Glycoside Hydrolases
poly ADP-ribose glycohydrolase