S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal
Authors Chen JK, Chen J, Thomas G, Kozma SC, Harris RC
Submitted By Raymond Harris on 8/11/2010
Status Published
Journal American journal of physiology. Renal physiology
Year 2009
Date Published 9/1/2009
Volume : Pages 297 : F585 - F593
PubMed Reference 19474189
Abstract Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA
replication, in all nephron segments of the remaining kidney, resulting in cell
growth (increase in cell size) with minimal cell proliferation (increase in cell
number). In addition to the compensatory renal hypertrophy caused by nephron
loss, pathophysiological renal hypertrophy can occur as a consequence of early
uncontrolled diabetes. However, the molecular mechanism underlying renal
hypertrophy in these conditions remains unclear. In the present study, we report
that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following
either contralateral nephrectomy or induction of diabetes. In wild-type mice,
hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6
(rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1(-/-)
mice exhibited moderately elevated basal levels of rpS6, which did not increase
further in response to the hypertrophic stimuli. Northern blotting indicated a
moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice.
Phosphorylation of the eukaryotic translation initiation factor 4E-binding
protein 1, another downstream target of the mammalian target of rapamycin
(mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+)
littermates during renal hypertrophy, indicating that mTOR was still activated
in the S6K1(-/-) mice. The highly selective mTOR inhibitor, rapamycin, inhibited
increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in
wild-type mice but failed to prevent the approximately 10% hypertrophy seen in
S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the
basal rpS6 phosphorylation. Thus the present study provides the first genetic
evidence that S6K1 plays a major role in the development of compensatory renal
hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and
diabetes-mediated mTOR activation can selectively activate S6K1 without
activating S6K2.

Investigators with authorship
Raymond HarrisVanderbilt University