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

Abstract

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-β1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (~260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg·kg -1 ·day -1 (D0.01, N = 14), 1 mg·kg -1 ·day -1 (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-β1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40%), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28% (P < 0.0001) and GLUT2 by 76% (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P ≤ 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-β1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.

GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

“…Furthermore, in 2010, Wang et al [11] linked GLUT1 expression and mesangial cell stretch to VEGF production and an associated increase in matrix protein synthesis, providing an additional conduit for Ang II induction of both GLUT1 and matrix protein synthesis. Finally, studies with ramipril in vivo and losartan in vitro have indicated that inhibition of angiotensin-converting enzyme or angiotensin receptor-1 can suppress renal cortical GLUT1 [41] and mesangial glucose uptake [42], respectively. Ramipril reduced renal cortical angiotensin-converting enzyme activity and GLUT1 expression in diabetic, hypertensive rats [41], while losartan blunted the effects of high glucose on mesangial cell GLUT1, GLUT4, glucose uptake and fibronectin expression [42].…”

An Experimental Model Study: Histomorphological and Ultrastructural Renal Changes in 1/2-5/6 Nephrectomized and Diabetic Rats

“…20,21 These diseases have effects on the kidneys such as glomerular hyperfiltration, increased glomerular capillary pressure, structural changes in glomeruli, increase in extracellular matrix, GBM thickening, enlargement of mesangial matrix and fibrosis. 15,20,21 Taking relationship between the kidney and hypertension into account, renal autoregulation is provided in essential hypertension and renal damage does not occur unless malignant hypertension develops. When the amount of kidney mass decreases and in the presence of diabetes mellitus, the pathophysiology of hypertensive renal damage changes.…”

“…[14][15][16] We have observed an increased renal damage in diabetes-induced rats both by light microscopic and electron microscopic evaluation. The effect of hypertension on renal injury alone is controversial while in rats with diabetic nephropathy, addition of systemic hypertension causes an increasing rate of glomerulosclerosis.…”

“…29 Souza et al induced diabetes by applying 50 mg/kg STZ to spontaneously hypertensive rats and examined GLUT-1 expression in renal cortex. 15 In an-Histology and Embryology Cilaker Micili et al…”

“…Increased renal damage is parallel with these two diseases. [14][15][16] Recently, renal damage is evaluated by addition of partial or total nephrectomy to STZ-induced diabetes models.…”