The link between mechanical stretch and glucose metabolism--a conceptual advance in understanding diabetic (and non diabetic?) renal disease

Diabetic kidney disease is today the most common cause of end-stage renal failure in many countries of the world and the number of diabetic patients in need of renal replacement therapy has increased over the last two decades [1]. Haemodynamic forces are major contributors to the development of renal damage in diabetes [2] and in other chronic glomerulopathies characterized by increased intraglomerular capillary pressure [3]. In most renal diseases, the increased glomerular pressure affects surviving glomeruli following an initial disease-induced nephron loss. In diabetes, intraglomerular hypertension occurs early as a result of hyperglycaemia-induced disruption of glomerular capillary autoregulatory mechanisms [4]. Under physiological euglycaemic conditions the pressure within the glomerular circulation is maintained stable by vasoregulatory mechanisms at the afferent and efferent arterioles which serve to protect the glomerulus from increases in systemic arterial blood pressure. This is usually obtained by commensurate vasoconstriction of the afferent arteriole. In diabetes, the expression of a number of molecules such as nitric oxide [5], bradykinins [6], prostaglandins [7] and transforming growth factor-β1 (TGF-β1) [8], involved in the regulation of vascular tone is altered, and contributes to the overall glomerular arteriolar vasodilatatory effects [7]. In this context, the activation of the renin angiotensin system (RAS) and in particular the local RAS contributes to altered glomerular haemodynamics [7]. The efferent glomerular arteriole is 10–100 times more sensitive to the action of angiotensin (Ang)-II, a potent vasoconstrictor, and this in itself results in an imbalance in arteriolar tone which leads to increased intraglomerular pressure [9,10]. This phenomenon is aggravated by the diabetes-induced inability of the afferent arteriole to vasoconstrict effectively in response to rises in systemic blood pressure. Thus, in diabetes, raised systemic blood pressure levels are readily transmitted to the glomerular capillary circulation. There is robust experimental evidence, with or without diabetes that when this condition occurs severe glomerular damage ensues [9,11,12]. Diabetes, via high blood glucose levels and its metabolic consequences, also induces per se glomerular damage. Although physiologically, haemodynamic and metabolic factors appear to concur in generating microvascular injury in the kidney, little is known, at the molecular level, of the mechanism(s) by which these factors interact or whether there is interaction at all, rather than just parallel effects. Non-diabetic animal models of systemic and glomerular hypertension such as the Dahl salt-sensitive (DSS) rats [13] develop renal lesions which have striking similarities with those seen in the diabetic animal. We were intrigued by the possibility that a mechanical insult might activate expression in the glomerulus of molecules involved in glucose uptake and metabolism. We considered that the glucose transporter GLUT-1 would be of interest in as much as it regulates the basal rate of glucose transport into the cell [14], an event which is particularly relevant for glucose metabolism of cells in the vessel wall and in the glomerulus where glucose uptake is relatively insulin-independent [15]. GLUT-1 is a member of the facilitative glucose transporter family, ubiquitously expressed with a cell distribution residing mainly in the plasma membrane [14]. GLUT-1 is a high-affinity, low-capacity glucose transporter which is at or near saturation at physiological glucose levels [14]. Therefore, changes in GLUT-1 expression, translocation or intrinsic activity are a prerequisite for changes in basal glucose uptake [15]. An increased expression in glomerular GLUT-1 levels in response to a mechanical stimulus would contribute to increase glucose transport, increase glucose uptake and activate different intracellular metabolic pathways magnifying the effect of glucose at any level of plasma concentration. The glomerulus is a complex structure, the stability of which depends on the cooperative function of several cell types (endothelial cells, mesangial cells and podocytes) and the glomerular basement membrane. All these cells are haemodynamically responsive [16–19] with mesangial cells, because of their anatomical distribution, as an important target for blood pressure-mediated changes within the glomerular capillaries [20]. In a recent study, we found that glomerular GLUT-1 expression was nearly doubled in hypertensive DSS rats when compared with the normotensive DSS control rats [18]. No difference was detected when comparing spontaneous hypertensive rats (SHR), a model of systemic hypertension with normal intraglomerular pressure to their Whistar Kyoto normotensive controls. Glomerular expression of TGF-β1, a potent prosclerotic cytokine, was ∼2.5-fold higher in the hypertensive DSS vs their respective normotensive controls whereas TGF-β1 was barely detectable in the SHR and their normal controls [18]. When we applied mechanical stretch to human mesangial cells in vitro, we observed upregulation in the expression of GLUT-1 which was accompanied by a significant increase in cell glucose uptake [18]. We went on to demonstrate [21] that increased internalization of glucose would activate a sequence of intracellular metabolic pathways that, via activation of protein kinase C (PKC), up-regulated TGF-β1 and resulted in excess extracellular matrix (ECM) production [22]. Of great interest, evidence from our and other groups suggests that TGF-β1, in turn, via its own TGF-β1 receptor-II, would contribute to the upregulation of GLUT-1 expression thus triggering a vicious cycle resulting in higher cellular glucose transport and metabolism [18,23]. The results of these studies, diagrammatically depicted in Figure 1, clearly established that a haemodynamic stimulus, via overexpression of GLUT-1 glucose transporter, magnifies intracellular glucose metabolism for any given level of prevailing glycaemia. We postulated that a stretched human mesangial cell would sense a glucose concentration higher than the actual ambient glucose. It has not escaped our notice that this process may well apply to other glomerular cells subjected to a mechanical stimulus. Cellular pathways mediating mechanical stretch-induced GLUT-1 upregulation in mesangial cells. Mechanical stretch up-regulates GLUT-1 expression which leads to increased glucose transport/metabolism and, via activation of PKC, to overexpression of TGF-β1 and ECM production. TGF-β1, in turn, by binding to its own TGF-β1-typeII receptor maintains up-regulation of GLUT-1 expression and perpetuates a vicious circle eventually resulting in sclerosis. In diabetes, the situation is further aggravated by the fact that high glucose per se up-regulates GLUT-1 expression in mesangial cells [24]. Indeed, overexpression of GLUT-1 in mesangial cells cultured in normal glucose concentrations augments the basal glucose transport and results in increased ECM protein expression [25]. In contrast, overexpression of an antisense GLUT-1 mRNA in mesangial cells prevents glucose uptake as well as the glucose-induced ECM production [26]. In vivo diabetic db/db mice carrying an antisense GLUT-1 transgene are protected against the development of glomerular damage [27], while transgenic overexpression of GLUT-1 in glomeruli of non-diabetic animals produces a degree of glomerulopathy with mesangial expansion and increased proteinuria [28]. This positive mechanical–metabolic cooperativity, which results in excess matrix production, not only provides a mechanism for the injurious interaction of haemodynamic forces with hyperglycaemia in diabetes, but also suggests that glucose-related metabolic pathways may be involved in damage in non-diabetic glomerulopathies characterized by increased glomerular pressure. Interestingly, there is some evidence that polymorphisms in the GLUT-1 gene [29] may predispose to nephropathy. In the aggregate, our studies support the notion of an auto-maintaining cycle whereby haemodynamic perturbations amplify abnormalities of intracellular glucose metabolism through overexpression of GLUT-1 transporters, a process that leads to and is sustained by excess TGF-β1 production. These observations have clear clinical implications in as much as they underscore the critical importance of reducing, and ideally normalizing, systemic as well as glomerular hypertension as a prime target to break the vicious interaction of haemodynamic with metabolic factors. Inhibition of RAS appears central to this process. Conflict of interest statement. None declared.