Mitogen-activated protein kinases as glucose transducers for diabetic complications

Abstract

The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

“…ERK plays a pivotal role in activating mesangial TGF-β expression/signalling and extracellular matrix accumulation [29,30]. We clearly show that ERK activation in the kidney tissue was significantly attenuated in BNP-Tg mice (Fig.…”

“…Renal ERK activation Accumulating evidence indicates that activation of the ERK/MAPK signalling pathway plays a key role in the induction of Tgfb1 and extracellular matrix accumulation in diabetic nephropathy [29][30][31]. To address the mechanisms by which Tgfb1 and matrix gene expression was inhibited in BNP-Tg mice, we investigated the phosphorylation of ERK in the kidney.…”

Superoxide as a Messenger of Endothelial Function

“…Of course signal transduction and intracellular crosstalk by PKC dependent phosphorylation is manifold and complicated. The array of substrates involves enzymes, cell-surface receptors, contractile proteins, transcription factors and other kinases (Tomlinson, 1999;Idris et al 2001). Therefore in the present study only a few pathways had been explored as follows.…”

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

“…Any of these events could have an impact on Smad signaling. For example, elevated ERK activity, which can enhance Smad activity (19,21), has been reported in glomeruli from diabetic rats or in mesangial cells cultured with high-glucose medium (27)(28)(29).…”