| Authors |
Vashistha H, Singhal PC, Malhotra A, Husain M, Mathieson P, Saleem MA, Kuriakose
C, Seshan S, Wilk A, Delvalle L, Peruzzi F, Giorgio M, Pelicci PG, Smithies O,
Kim HS, Kakoki M, Reiss K, Meggs LG
|
| Submitted By |
Submitted Externally on 4/10/2013 |
| Status |
Published |
| Journal |
American journal of physiology. Renal physiology |
| Year |
2012 |
| Date Published |
12/15/2012 |
| Volume : Pages |
303 : F1629 - F1640 |
| PubMed Reference |
|
| Abstract |
Candidate genes have been identified that confer increased risk for diabetic
glomerulosclerosis (DG). Mice heterozygous for the Akita (Ins2(+/C96Y))
diabetogenic mutation with a second mutation introduced at the bradykinin 2
receptor (B2R(-/-)) locus express a disease phenotype that approximates human
DG. Src homology 2 domain transforming protein 1 (p66) controls mitochondrial
metabolism and cellular responses to oxidative stress, aging, and apoptosis. We
generated p66-null Akita mice to test whether inactivating mutations at the p66
locus will rescue kidneys of Akita mice from disease-causing mutations at the
Ins2 and B2R loci. Here we show null mutations at the p66 and B2R loci interact
with the Akita (Ins2(+/C96Y)) mutation, independently and in combination,
inducing divergent phenotypes in the kidney. The B2R(-/-) mutation induces
detrimental phenotypes, as judged by increased systemic and renal levels of
oxidative stress, histology, and urine albumin excretion, whereas the p66-null
mutation confers a powerful protection phenotype. To elucidate the mechanism(s)
of the protection phenotype, we turned to our in vitro system. Experiments with
cultured podocytes revealed previously unrecognized cross talk between p66 and
the redox-sensitive transcription factor p53 that controls hyperglycemia-induced
ROS metabolism, transcription of p53 target genes (angiotensinogen, angiotensin
II type-1 receptor, and bax), angiotensin II generation, and apoptosis.
RNA-interference targeting p66 inhibits all of the above. Finally, protein
levels of p53 target genes were upregulated in kidneys of Akita mice but
unchanged in p66-null Akita mice. Taken together, p66 is a potential molecular
target for therapeutic intervention in DG.
|
|
|