Mesangial Cellsignaling Pathways From Glucose Transporters To Extracellular Matrix Production

An isolated increase in MC glucose transporter expression (i.e., GLUT1) leads to persistent increases and activation of PKCa and PKCP, even in the absence of high extracellular glucose concentrations (57). A persistently elevated glucose uptake rate, polyol pathway activation with sorbitol accumulation, enhanced glycolysis, excessive glucose utilization, and excessive ECM production are also features of this model (25,57). Increased PKC activity is known to stimulate assembly of the transcriptional activator protein AP-1 from cfos and cjun (4), leading to increased AP-1 as described in GLUTl-overexpressing MC (49). The AP-1 can then bind to TPA-responsive elements

(i.e., TREs) in regulatory regions of target genes such as fibronectin and GLUT1 to increase their expression (49). AP-1 is persistently increased in mesangial cells over-expressing GLUT1 (49). Although acute increases in transforming growth factor (TGF)-P1, mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) in response to high extracellular glucose exposure have been implicated in excessive MC ECM production (5,58), these processes are not necessary for maintenance of excess MC ECM production in response to an isolated increase in GLUT1 expression (49). Preliminary work in which PKC was inhibited with Calphostin-C treatment and chronic PMA suppression indicated a role for PKC in GLUT1-induced GLUT1 gene transcription (59).

Therefore, in the long term there appears to be an important role for the PKC pathway in maintenance of glucose-induced ECM production. It is not yet known whether chronic, intermittent high-glucose exposure would cause recurrent increases in TGF-P1, MAPK, and ROS to stimulate MC ECM production, and this needs to be investigated. Potential roles for intracellular advanced glycosylation endproducts (AGE) and receptor for AGE (RAGE) expression also need to be examined with respect to MC glucose transporters and ECM expression, because AGE have been implicated in DN. Studies of serine/threonine Akt kinase signaling in nonrenal cell types have identified a role for this mediator in stimulating GLUT1 gene expression and translocation to the plasma membrane (60,61). Investigation of Akt signaling may therefore be of value in determining mechanisms by which glomerular GLUT1 is increased in diabetes.

As noted earlier, investigations are underway to identify GLUT1-responsive genes in MC and mechanisms by which they are induced. Finally, the USF transcription factors (i.e., upstream stimulatory factors) are being investigated to determine their roles in glucose- and GLUT1-induced gene expression in MCs, as a preliminary report suggests USF2 is regulated by glucose and glucose transporters in these cells (62).

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