Increased Urinary TGF-β1 and Cortical Renal GLUT1 and GLUT2 Levels: Additive Effects of Hypertension and Diabetes

Abstract

Background/Aim: Diabetes and mesangial stretch caused by hypertension increase mesangial matrix deposition which is induced by local production of transforming growth factor beta 1 (TGF-β1). Both conditions are associated with cortical GLUT1 overexpression. We evaluated the effect of genetically determined hypertension and its association with diabetes on urinary TGF-β1 and cortical GLUT1 and GLUT2 expression. Methods: We studied Wistar-Kyoto rats (controls, C) and spontaneously hypertensive rats (SHR), weighing ∼210 g, 30 days after the injection of streptozotocin (diabetic, D) or citrate buffer (10 C, 9 SHR, 12 C-D and 15 SHR-D). Twenty-four-hour urine was collected for glucose, albumin, and TGF-β1 determinations. Catheters were implanted into the femoral artery to measure the arterial blood pressure in conscious animals 1 day later. Then GLUT1 and GLUT2 protein levels (Western blotting) in renal cortex and medulla were evaluated. Results: The cortical GLUT1 levels were 5, 2, and 7 times higher in SHR, C-D, and SHR-D groups versus C group (p < 0.05); the GLUT2 contents were 1.5, 1.8, and 2.3 times higher in SHR, C-D and SHR-D groups versus C group (p < 0.05). The urinary TGF-β1 level was elevated by diabetes and diabetes and hypertension, but not by hypertension alone: 1.39 ± 0.2, 2.34 ± 0.6, 18.2 ± 3.2, and 28.8 ± 7.6 ng/24 h, respectively, in C, SHR, C-D, and SHR-D groups (p < 0.05). Conclusions: Diabetes, hypertension, and especially their association increase the renal cortical GLUT1 and GLUT2 levels. The magnitude of GLUT1 overexpression caused by hypertension is higher than that induced by diabetes alone. The impact on urinary TGF-β1 occurs when diabetes and hypertension are associated, suggesting an effect that is triggered in the presence of GLUT1 overexpression and hyperglycemia.

Preventive role of exercise training in autonomic, hemodynamic, and metabolic parameters in rats under high risk of metabolic syndrome development

“…Interestingly, renal sympathetic denervation in these animals contributed to lower GLUT2 expression. These data demonstrate the neural regulation effect in GLUT2 expression (31,32). Since exercise training decreased renal sympathetic activity, we may postulate that the FT rats are prevented from renal damage in relation to the sedentary ones.…”

Bases moleculares da glomerulopatia diabética

“…Estudos de nosso grupo demonstraram, in vivo, no modelo de diabetes por STZ em ratos, maior expressão de GLUT1 em córtex renal, associado à maior excreção urinária de TGF-β1 e microalbuminúria (21). O GLUT2, principal transportador responsável pela reabsorção tubular de glicose, também se encontra expresso no diabetes experimental (22), favorecendo aumento da glicose intersticial, a qual é transportada então para o interior das células mesangiais pela ação do GLUT1 (figura 1).…”

“…O GLUT2, principal transportador responsável pela reabsorção tubular de glicose, também se encontra expresso no diabetes experimental (22), favorecendo aumento da glicose intersticial, a qual é transportada então para o interior das células mesangiais pela ação do GLUT1 (figura 1). No modelo animal de hipertensão geneticamente determinada (ratos SHR) com diabetes por STZ, os resultados foram semelhantes, além de se observar um efeito aditivo da hipertensão sobre a hiperglicemia em aumentar a expressão de GLUT1 e GLUT2 (21). Estudos in vitro identificaram o GLUT1 como o principal transportador de glicose nas células mesangiais de camundongos (23) e humanos (24).…”

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

“…Subsequently, upregulation of cortical renal GLUT1 and GLUT2 levels and increased urinary TGF-β1 and albumin excretion in genetically hypertensive diabetic rats have been reported (17). The major effect of hypertension on GLUT1 overexpression could be mediated by AII, since it is elevated in the plasma of stroke-prone spontaneously hypertensive rats (SHR; 18) and, in vitro, it causes overexpression of GLUT1 in vascular smooth muscle (19) and in mesangial cells (20).…”