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Endocrinology Vol. 149, No. 3 913-916
Copyright © 2008 by The Endocrine Society

Glucose Transporter 12 and Mammalian Target of Rapamycin Complex 1 Signaling: A New Target for Diabetes-Induced Renal Injury?

Helena Schmid, Marcello Bertoluci and Terezila Machado Coimbra

Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (H.S.) Programa de Pós-Graduação em Ciências Médicas Santa Casa de Porto Alegre Porto Alegre, Brasil 90020090, and Universidade Federal do Rio Grande do Sul Programa de Pós-Graduação em Ciências Médicas (H.S., M.B.) Hospital de Cínicas de Porto Alegre Porto Alegre, Brasil 90035003, and Faculdade de Medicina de Ribeirão Preto (T.M.C.) Universidade de São Paulo São Paulo, Brasil 14049900

Address all correspondence and requests for reprints to: Dr. Helena Schmid, Fundação Faculdade Federal de Ciências Médicas de Porto Alegre, Programa de Pós-Graduação em Ciências Médicas, Santa Casa de Porto Alegre, Professor Annes Dias, 285, Porto Alegre, Brasil 90020090. E-mail: schmidhelena{at}yahoo.com.br.

Diabetic nephropathy is one of the major causes of end-stage renal disease, affecting approximately one third of patients with type 1 and a significant number of patients with type 2 diabetes (1). Both hyperglycemia and hypertension are known to be related to its development (2), via oxidative stress (3), enhanced TGF-β1 production (4), mesangial stretch reflecting glomerular hypertrophy and hypertension (5), activation of the renin-angiotensin system (6), and elevated glucose in the mesangial cells milieu (7). Increased protein tubular reabsorption leading to interstitial inflammation and the up-regulated glucose transport in the diabetic kidney, in response to hyperglycemia, also contribute to the evolution of renal disease (8).

Characteristic pathological findings in the diabetic kidney are early hypertrophy plus progressive glomerular and tubulointerstitial fibrosis, with thickening of glomerular basement membranes and progressive expansion of the glomerular mesangium (9, 10). In vivo and in vitro studies provide evidence that ambient high glucose induces the synthesis of these extracellular matrix components (e.g. fibronectin) in both glomerular and proximal tubular compartments (11, 12). Glomerular basal membrane thickening after glycoprotein deposition may decrease the electrical charge of the glomerular basement membrane and thus be the initial step in the development of progressive albuminuria in human diabetes and animal models of experimental diabetic nephropathy (13). Several of the adverse effects of both hyperglycemia and albuminuria have been linked to the enhanced action of the prosclerotic cytokine TGF-β1 (14).

Glucose reaches kidney cells via arterial blood and renal tubular glucose reabsorption. This reabsorption is mediated by facilitative glucose transporter (GLUT) proteins and energy-dependent sodium glucose luminal transporters. In diabetic hyperglycemic rats, modulation of GLUT1, GLUT2, and the fructose-specific transporter GLUT5 has been reported in response to high intracellular concentration of glucose (14, 15). Strict prevention of hyperglycemia and microalbuminuria can prevent the onset and progression of diabetic nephropathy (16).

In this issue of Endocrinology, in an elegant model, using Madin-Darby canine kidney (MDCK) polarized renal tubular epithelial cells, Wilson-O’Brien, DeHaan, and Rogers (17) demonstrated that GLUT12, a newly identified class III glucose transporter, is involved in regulation of glucose flux in distal renal tubules in response to an increased-glucose medium. The authors showed that in distal tubular cells, high glucose exposure translocates GLUT-12 from the perinuclear region to the apical membrane and that this effect was related to increased-glucose medium independent of osmolarity. Importantly, it was possible to inhibit the mitogen-stimulated targeting of GLUT-12 by blocking the function of the mammalian target of rapamycin (mTor) complex1-S6k1 signaling, known to be under the control of nutrient and energy input. Using GLUT-12 cDNA containing a c-Myc epitope, glucose transport at the apical membrane was also measured in this study. By the use of a neutralizing anti-c-Myc monoclonal antibody, GLUT-12-mediated glucose transport was shown to be mitogen dependent and rapamycin sensitive. The authors concluded that there is probably a link between GLUT-12 protein trafficking, glucose transport, and signaling molecules that control metabolic disease processes in the renal tubule.

A previous study from Linden et al. (18) evaluated the renal expression and localization of the facilitative glucose transporters GLUT1 and GLUT12 in animal models of hypertension and diabetic nephropathy. Both wild-type Sprague Dawley rats and transgenic Sprague Dawley rats with hypertension after insertion of the mouse ren2 gene into their genome received either streptozotocin or vehicle. GLUT1 immunolabeling was detected on the basolateral membrane throughout the nephron. GLUT-12 was localized at the apical membrane of distal tubules and collecting duct cells, with an increase in GLUT-12 immunolabeling found both in Ren-2 controls and Ren-2 diabetic animals compared with wild-type. GLUT-12 expression was also higher in Ren-2 diabetic than Sprague Dawley diabetic rats. Long-term diabetes produced significant increases in GLUT-1 levels in the renal proximal tubules, with higher expression in Ren-2 diabetic than wild-type diabetic rats. Because the GLUT-12 protein is on the apical membrane of distal tubular and collective duct cells, and both GLUT1 and GLUT12 are elevated in animal models of hypertension and diabetic nephropathy, the authors speculated that the apical localization of GLUT-12 might contribute to additional glucose reabsorption in the distal nephron (18).

TGF-β production by tubule cells in response to a high glucose load can induce interstitial inflammation and fibrosis (19). It is not yet clear whether increased intracellular glucose in distal tubular cells can also affect mesangial cell metabolism; however, it is possible that increased TGF-β production by tubular cells may facilitate the activation of intracellular signaling pathways in mesangial cells, particularly given their localization close to the mesangium (Fig. 1Go).


Figure 1
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  		FIG. 1. Sequence of classical glomerular responses involved in renal hypertrophy, progressive glomerular and tubulo-interstitial fibrosis, with thickening of glomerular basement membranes and progressive expansion of the glomerular mesangium. DAG, diacylglycerol; PKC, protein kinase C; TGF-β, transforming growth factor β; A-II, angiotensin II; ECM, extracellular matrix.

 
We have thus investigated the distribution of TGF-β1 protein and mRNA levels in the glomeruli and renal cortex of Wistar rats with streptozotocin-induced diabetes over the course of diabetic nephropathy. Progressively higher glomerular and tubulointerstitial TGF-β staining was seen after 24 and 40 wk, correlating with albuminuria and was temporally associated with the appearance of glomerular deposition of total and type I collagen; in addition, glomerular TGF-β1 mRNA content was higher in rats with diabetes for 20 wk (20). Another study showed that treatment with angiotensin II antagonists may modify events preceding diabetic nephropathy by reducing TGF-β and fibronectin expression in glomeruli and in tubulointerstitium in parallel with urinary TGF-β in these animals (6), evidence that TGF-β1 may be an important mediator of diabetic glomerulosclerosis (6, 20). Hyperglycemia was also shown to elevate TGF-β1, which probably stimulates the production of fibronectin and other matrix proteins in mesangial and other renal cells (6). Activation of protein kinase C (PKC) isoforms (21), the hexosamine biosynthetic pathway (22), ERK1 and -2 (23), and the p38 MAPK pathway (24) have all been implicated in the enhanced expression of TGF-β1 and matrix proteins. Of note, hyperglycemia-enhanced generation of reactive oxygen species has been linked to activation of PKC (25) and the hexosamine pathway (26) and to enhanced TGF-β1 synthesis (27).

There is also other evidence linking the increased glucose metabolism to the pathological changes of diabetic nephropathy. Because glucose transport is rate limiting for glucose metabolism, and because GLUT1 is the main isoform on mesangial cells and a high-affinity, low-capacity transporter, mesangial glucose uptake is essentially determined by the number of GLUT1 on the cell surface rather than ambient glucose concentration (28). Accordingly, up-regulation of GLUT1 in these cells is a major factor in increased matrix production. In cultured mesangial cells, ambient high glucose concentrations increase GLUT1 expression and thus also increased basal glucose uptake (29).

Although little is known about the cellular expression pattern of GLUT1 in the diabetic kidney, we have previously reported increased GLUT1 protein in the renal cortex of diabetic animals (30). Because hyperglycemia can induce TGF-β1 synthesis (27) and TGF-β can (31) stimulate GLUT1 expression, a self-perpetuating cycle might occur in the kidneys of patients with diabetes (Fig. 1Go). It is therefore possible that part of the increased TGF-β1 production by the diabetic kidney may be secondary to the GLUT12-mediated tubular response of increased reabsorption of glucose (Fig. 2Go). In this context, the mTor pathway activation could be an important link between hyperglycemia and the renal hypertrophy seen in diabetic nephropathy as well as renal fibrosis through TGF-β1 signaling.


Figure 2
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  		FIG. 2. Cells of the distal tubule express GLUT 12 and might promote glucose reabsorption with secondary tubular hypertrophy and possible autocrine responses in mesangial cells.

 
Future treatment strategies for preventing diabetic nephropathy using mTor-complex 1 signaling blockers might thus be an interesting avenue of research.


   Footnotes
 
See article p. 917.

Abbreviations: GLUT, Glucose transporter; mTor, mammalian target of rapamycin; PKC, protein kinase C.

Received December 11, 2007.

Accepted for publication January 2, 2008.


   References
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