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

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.