Abstract
BackgroundInsulin receptor (InsR) and insulin signaling proteins are widely distributed throughout the kidney cortex. Insulin signaling can act in the kidney in multiple ways, some of which may be totally independent of its primary role of the maintenance of whole-body glucose homeostasis. However, descriptions of the insulin signaling in renal glomerular mesangial cells (MCs) are quite limited and the roles of insulin signaling in MC functions have not been sufficiently elucidated.ResultsInsR silencing induced a unique phenotype of reduced fibronectin (FN) accumulation in renal glomerular MCs. Transcription level of FN was not significantly changed in the InsR silenced cells, suggesting the phenotype switching was caused by post-transcriptional modification. The decreased expression of InsR was associated with enhanced activity of insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt signaling pathway which contributed in part to the attenuation of cellular FN accumulation. Formation of IGF-1R homodimer was increased in the InsR silenced cells. The InsR silenced cells also showed increased sensitivity to exogenous IGF-1, and increased PI3K activity was reversed significantly by incubating cells with IGF-1R specific antagonist, AG538. PI3K/Akt dependent activation of cAMP responsive element-binding protein (CREB)-1 induced expression of matrix metalloproteinase (MMP)-9 and suppressing MMP activity by doxycycline partially reversed FN accumulation in the InsR silenced cells.ConclusionsThe effects of InsR silencing on cellular FN accumulation in vitro are, at least partially, mediated by increased degradation of FN by MMPs which is induced by enhanced signaling sequence of IGF-1R/PI3K/Akt/CREB-1.
Highlights
Insulin receptor (InsR) and insulin signaling proteins are widely distributed throughout the kidney cortex
Inhibition of matrix metalloproteinase (MMP) with doxycycline in InsR silenced cells effectively reversed the reduction in intracellular FN levels to about 70% of that of scrambled oligo plasmid (SC) cells (Figure 6D). These findings suggest that the attenuated cellular accumulation of FN in the InsR silenced cells was partially dependent on increased degradation by MMP which was induced by insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt/cAMP responsive element-binding protein (CREB)-1 signaling pathways
Our data suggest that the altered balance in the formation of InsR/IGF-1R homodimer and hybrid receptor is a crucial factor in the phenotype switching in mesangial cells (MCs)
Summary
Insulin receptor (InsR) and insulin signaling proteins are widely distributed throughout the kidney cortex. The mechanisms responsible for the ECM protein deposition are still inconclusive, the role of renal glomerular mesangial cells (MCs) in this sclerotic change has been gathering increasing attentions. MMPs and their specific inhibitors, tissue inhibitor of metalloproteinases (TIMPs), play an important role in regulating glomerular matrix remodeling [5,9,10]. Based on these findings, besides their three primary functions, that is, filtration, structural support, and phagocytosis, MCs have been postulated to be a key player for FN regulation in the kidney and is speculated as one of the major contributors to the sclerotic lesion in glomeruli [11]
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