c-myc antisense oligonucleotide treatment ameliorates murine ARPKD.
BACKGROUND
Overexpression of c-myc is postulated to play a role in the pathogenesis of polycystic kidney disease (PKD). c-myc expression is increased in all rodent models of PKD that have been examined as well as in human ADPKD. To determine whether overexpression of renal c-myc contributes to renal cyst formation, C57BL/6J-cpk litters (an animal model of ARPKD) were treated with an antisense oligomer (ASO) to c-myc mRNA.


METHODS
Injections of 30 microg of a c-myc ASO were given to C57BL/6J-cpk litters on postnatal days 7-20. Control mice received either sham injections or injections of an equal amount of a scrambled ASO. At 20 days, kidney weight, body weight, serum urea nitrogen (SUN), hematocrit, and renal concentration of ASO were determined. In kidney, c-Myc and PCNA protein were assessed by immunoblotting and steady state levels of renal RNA for c-myc, EGF, SGP-2, and histone H4 were assessed by northern blot hybridization. c-Myc and PCNA proteins were localized by immunohistochemistry.


RESULTS
Cystic mice treated with the c-myc ASO had a decreased relative kidney weight, improved renal function, and a reduced amount of cystic change compared with sham and scrambled ASO controls. The abnormal expression of several PKD related proteins and mRNAs were partially reversed by c-myc antisense treatment. c-myc staining appeared to be reduced in the noncystic tubules. Treatment with the c-myc ASO did not cause a reduction in hematocrit or total body weight indicating that the beneficial effects were not due to a generalized inhibition of cell proliferation in rapidly growing tissue.


CONCLUSIONS
c-Myc appears to play a role in the cystogenesis of cpk-induced murine PKD and antisense targeting the overexpression of c-myc partially ameliorated the renal changes.
Ricker
Justin L
JL
Department of Anatomy and Cell Biology, The University of Kansas Medical Center, Kansas City, Kansas 66160-7400, USA.
Mata
John E
JE
Iversen
Patrick L
PL
Gattone
Vincent H
VH
D000818:Animals; D016259:Genes, myc; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy*
D016376:Oligonucleotides, Antisense