GLUT-1 and TGF-ß: the link between hyperglycaemia and diabetic nephropathy

Giovanni Gambaro, Monica Ceol, Dorella Del Prete and Angela D'Angelo

Divisione di Nefrologia, Istituto di Medicina Interna, Universita di Padova, Padova, Italy

Sir,

Mogyorósi and Ziyadeh have recently published a quite interesting hypothesis on the role of the interaction between TGF-ß and GLUT-1 in the pathogenesis of diabetic nephropathy [1]. Its interest is even higher if one considers the possibility of a third factor in this severe disease, namely, the renin–angiotensin system (RAS). The authors stated that a host of additional factors may modulate the deleterious effects of hyperglycaemia. The RAS most likely is, together with TGF-ß and GLUT-1, one of these. However, while clinical and experimental data support the existence of an interaction between diabetes and RAS, how this interaction precisely occurs is not clear. As a matter of fact, a number of observations demonstrate that angiotensin II-mediated signal transduction may be diminished, rather than augmented, in the presence of high glucose [2]. However, the demonstration that angiotensin II stimulates glucose uptake and the transcription of the glucose transporter GLUT-1 in various cells [3] raises the intriguing possibility that in diabetic patients a primarily increased activity of the RAS at the kidney level, for instance due to a particular genetic background, may secondarily lead to a higher intracellular glucose concentration than in diabetic subjects with a normal renal RAS. The consequences of such a phenomenon are multiple since a number of cellular abnormalities, including increased TGF-ß synthesis, which is believed to lead to diabetic nephropathy, depend on the level of intracellular glucose.

It is also clear now that the third factor, namely angiotensin II, is a potent inducer of TGF-ß and that some of its reported effects are directly mediated by the expression of this growth factor [4]. Available data suggest the hypothesis that TGF-ß constitutes the missing link between glomerular hyperfiltration, i.e. a pure haemodynamic and RAS-dependent event, and glomerulosclerosis.

The finding that angiotensin II up-regulates the expression of TGF-ß receptors is a further intriguing piece of this story [5]; by increasing the sensitivity of mesangial cells to TGF-ß, angiotensin II may be involved in the initiation of an TGF-ß autoinduction loop.

Finally, the RAS-dependent increased GLUT-1 expression may also feed this loop. As a consequence, a pernicious mechanism may be triggered in genetically predisposed diabetic patients, which ultimately leads to renal failure.

References

  1. Mogyorósi A, Ziyadeh FN. GLUT1 and TGF-ß: the link between hyperglycaemia and diabetic nephropathy. Nephrol Dial Transplant1999; 14: 2827–2829[Abstract/Free Full Text]
  2. Kikkawa R, Kitamura E, Fujiwara Y, Arimura T, Haneda M, Shigeta Y. Impaired contractile responsiveness of diabetic glomeruli to angiotensin II: a possible indication of mesangial dysfunction in diabetes mellitus. Biochem Biophys Res Commun1986; 136: 1185–1190[ISI][Medline]
  3. Low BC, Ross IK, Grigor MR. Angiotensin II stimulates glucose transport activity in cultured vascular smooth muscle cells. J Biol Chem1992; 267: 20740–20745[Abstract/Free Full Text]
  4. Kagami S, Border WA, Miller DA, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-ß expression in rat glomerular mesangial cells. J Clin Invest1994; 93: 2431–2437[ISI][Medline]
  5. Kanai H, Centrella M, Noble NA, Border WA. Angiotensin II upregulates the expression of TGF ß type I and II receptors. J Am Soc Nephrol1997; 8: 518 (abstract)

 

Reply

András Mogyorósi

Division of Nephrology, Department of Medicine, Virginia Commonwealth University, Medical College of Virginia and McGuire VAMC, Richmond, Virginia, USA

Sir,

In their Letter to the Editor, Gambaro et al. correctly point out the importance of the renin–angiotensin system (RAS) in diabetic kidney disease. Particularly interesting is the parallel Gambaro et al. draw between hyperglycaemia and an up-regulated RAS in terms of their similar augmenting effect on the abundance of GLUT-1 and TGF-ß. To further strengthen this notion, we recently found that high ambient glucose (just like angiotensin II) increases mRNA and protein levels of TGF-ß type II receptor in cultured mouse mesangial cells [1].

To rephrase our hypothesis [2] by incorporating the remarks of Gambaro et al. one can state that the vehicle of diabetic nephropathy rests on a TGF-ß–GLUT1 axis that is propelled forward by numerous interconnected engines, the most important ones being hyperglycaemia and an up-regulated RAS. Putting an engine brake on this vehicle in the form of more intense glucose control proved to be beneficial in preventing the development and slowing the progression of the disease [3]. Attenuating the activity of the RAS by angiotensin converting enzyme inhibition yields similar results in both type 1 and type 2 diabetic patients with diabetic nephropathy [4,5] (whether angiotensin II type 1 receptor blockers will have the same effect is not yet known [6]). As correctly pointed out by Gambaro et al. however, it is important to realize that, since only a minority of patients with type 1 or type 2 diabetes mellitus ever develop nephropathy, genetic susceptibility to diabetic kidney disease likely plays a significant role. Whether this manifests in altered activity of TGF-ß, RAS, or GLUT-1, remains one of the cornerstone questions in the research of diabetic nephropathy.

References

  1. Isono M, Mogyorósi A, Han DC, Hoffman BB, Ziyadeh FN. Stimulation of TGF-beta type II receptor gene expression in mouse mesangial cells by high glucose and in diabetic kidney. Am J Physiol (in press)
  2. Mogyorósi A, Ziyadeh FN. GLUT1 and TGF-ß: the link between hyperglycemia and diabetic nephropathy. Nephrol Dial Transplant1999; 14: 2827–2829[Abstract/Free Full Text]
  3. DCCT. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med1993; 329: 977–986[Abstract/Free Full Text]
  4. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med1993; 329: 1456–1462[Abstract/Free Full Text]
  5. Ravid M, Savin H, Jutrin I et al. Long-term effect of ACE inhibition on development of nephropathy in diabetes mellitus type II. Kidney Int1994; 45 [Suppl]: S161–S164[ISI]
  6. Mogyorósi A, Sonkodi S. AT1 receptor antagonists: a challenge for ACE inhibitors in diabetic nephropathy. Diabetes Metab Res Rev1999; 15: 55–58[ISI][Medline]