S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy

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.

Loss of Primary Cilia Upregulates Renal Hypertrophic Signaling and Promotes Cystogenesis

“…Consistent with the studies of Chen et al, 18,19 we found that unilateral nephrectomy increased mTOR activity. Additionally, we found that mTOR activity also increased upon deletion of cilia.…”

“…Recent studies by Chen et al 18,19 have provided persuasive evidence that elevated mTOR activity is involved in renal hypertrophic responses to unilateral nephrectomy or to the induction of diabetes. Importantly, knockout of S6 kinase, a key enzyme downstream from mTOR, effectively eliminates most hypertrophy in response to nephrectomy.…”

“…9,15,16 However, recovery from acute kidney injury is a multifactorial process including loss of normal renal architecture, disruption of cell-tomatrix and cell-to-cell interactions, necrosis, apoptosis, and recruitment of a myriad of hormones and autocoids. 17 Recent studies 18,19 have indicated that the mammalian target of rapamycin (mTOR) 20 may be one important factor that mediates the hypertrophic response to unilateral nephrectomy. To support this contention, inhibition of the mTOR pathway significantly inhibited renal hypertrophy found in response to unilateral nephrectomy or in diabetes.…”

“…To support this contention, inhibition of the mTOR pathway significantly inhibited renal hypertrophy found in response to unilateral nephrectomy or in diabetes. 18 Although regulated mTOR activity appears to play an important role in hypertrophy, a physiologically adaptive response, dysregulated mTOR is also involved in certain diseases, including tuberous sclerosis complex and cancer 21,22 ; mTOR has also been implicated in the pathogenesis of PKD. [23][24][25][26] This suggests that there may be a link between mTOR signaling, hypertrophy, and cystogenesis.…”

Blocking rpS6 Phosphorylation Exacerbates Tsc1 Deletion–Induced Kidney Growth

“…16 Their results demonstrated that uninephrectomy induced mTORC1 signaling and renal hypertrophy without cyst formation in wild-type (WT) mice; however, uninephrectomy activated excessive mTORC1 signaling, triggered increased renal hypertrophy and accelerated renal cyst formation, leading to renal dysfunction in conditional ift88 knockout mice. 16 Of interest, mTORC1 activation also mediates both diabetes-induced renal growth [17][18][19] and phosphatase and tensin homolog deletion-induced renal growth. 15 Homozygous knockout of S6K1 blunts both uninephrectomyand diabetes-induced renal growth, 17 and phosphorylated rpS6 is a major effector downstream of mTORC1 activation in mediating compensatory renal growth.…”