| First Author | Chen L | Year | 2019 |
| Journal | Biochem Pharmacol | Volume | 167 |
| Pages | 116-124 | PubMed ID | 31326434 |
| Mgi Jnum | J:286114 | Mgi Id | MGI:6390384 |
| Doi | 10.1016/j.bcp.2019.07.003 | Citation | Chen L, et al. (2019) Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice. Biochem Pharmacol 167:116-124 |
| abstractText | 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 9.5days 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 3months 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. |
