Regulation of glucose uptake in mesangial cells stimulated by high glucose: role of angiotensin II and insulin.
Mesangial cells (MCs) play a central role in the pathogenesis of diabetic nephropathy (DN). MC dysfunction arises from excessive glucose uptake through insulin-independent glucose transporter (GLUT1). The role of the insulin-dependent transporter (GLUT4) remains unknown. This study evaluated the effect of high glucose on GLUT1, GLUT4, and fibronectin expression levels. Glucose uptake was determined in the absence and presence of insulin. Angiotensin II has been implicated as a mediator of MC abnormalities in DN, and its effects on the GLUTs expression were evaluated in the presence of losartan. MCs were exposed to normal (NG, 10 mM) or high (HG, 30 mM) glucose for 1, 4, 12, 24, and 72 hrs. Glucose uptake was elevated from 1 hr up to 24 hrs of HG, but returned to NG levels after 72 hrs. HG induced an early (1-, 4-, and 12-hrs) rise in GLUT1 expression, returning to NG levels after 72 hrs, whereas GLUT4 was overexpressed at later timepoints (24 and 72 hrs). HG during 4 hrs induced a 40% rise in glucose uptake, which was unaffected by insulin. In contrast, after 72 hrs, glucose uptake was increased by 50%, only under insulin stimulus. Losartan blunted the effects of HG on GLUT1, GLUT4, and fibronectin expression and on glucose uptake. Results suggest that MCs can be highly susceptible to the HG environment since they uptake glucose in both an insulin-independent and insulin-dependent manner. The beneficial effects of angiotensin II inhibition in DN may also involve a decrease in the rate of glucose uptake by MCs.
Arnoni
Carine P
CP
Federal University of São Paulo, Renal Division, 04023-900 - São Paulo, SP, Brazil.
Lima
Carla
C
Cristovam
Priscila C
PC
Maquigussa
Edgar
E
Vidotti
Daniela B
DB
Boim
Mirian A
MA
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D005353:Fibronectins / Q000096:biosynthesis; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D005353:Fibronectins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D000804:Angiotensin II; D005947:Glucose; D019808:Losartan