Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF

Abstract

Reduced nephron numbers may predispose to renal failure. We hypothesized that glucose transporters (GLUTs) may contribute to progression of the renal disease, as GLUTs have been implicated in diabetic glomerulosclerosis and hypertensive renal disease with mesangial cell (MC) stretch. The Os (oligosyndactyly) allele that typically reduces nephron number by ∼50%, was repeatedly backcrossed from ROP (Ra/+ (ragged), Os/+ (oligosyndactyly), and Pt/+ (pintail)) Os/+ mice more than six times into the Fvb mouse background to obtain Os/+ and +/+ mice with the Fvb background for study. Glomerular function, GLUT1, signaling, albumin excretion, and structural and ultrastructural changes were assessed. The FvbROP Os/+ mice (Fvb background) exhibited increased glomerular GLUT1, glucose uptake, VEGF, glomerular hypertrophy, hyperfiltration, extensive podocyte foot process effacement, marked albuminuria, severe extracellular matrix (ECM) protein deposition, and rapidly progressive renal failure leading to their early demise. Glomerular GLUT1 was increased 2.7-fold in the FvbROP Os/+ mice vs controls at 4 weeks of age, and glucose uptake was increased 2.7-fold. These changes were associated with the activation of glomerular PKCβ1 and NF-κB p50 which contribute to ECM accumulation. The cyclic mechanical stretch of MCs in vitro, used as a model for increased MC stretch in vivo, reproduced increased GLUT1 at 48 h, a stimulus for increased VEGF expression which followed at 72 h. VEGF was also shown to act in a positive feedback manner on MC GLUT1, increasing GLUT1 expression, glucose uptake and fibronectin (FN) accumulation in vitro, whereas antisense suppression of GLUT1 largely blocked FN upregulation by VEGF. The FvbROP Os/+ mice exhibited an early increase in glomerular GLUT1 leading to increased glomerular glucose uptake PKCβ1, and NF-κB activation, with excess ECM accumulation. A GLUT1–VEGF–GLUT1 positive feedback loop may play a key role in contributing to renal disease in this model of nondiabetic glomerulosclerosis.

GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

“…In this regard, an increase in GLUT1 expression has been observed following mesangial cell stretch [11] and in conjunction with a nephron-deficient mouse model with glomerular hypertension and hyperperfusion [11,37] and in Milan normotensive rats [38,39], all of which would be an expected result of Ang II vasoactivity [40]. 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.…”

“…Mesangial cell stretch activates both GLUT1 and TGF-β [11,46] and may reactivate or bolster the above amplification cycle. Taken together, TGF-β may trigger GLUT1 through MAPK and/or mesangial cell stretch.…”

“…This implies that upregulation of GLUT1, through an increase in glucose flux, may result in an increase in CTGF by stimulating TGF-β, suggesting a potential role for GLUT1 in this activation loop. The mechanism by which mechanical strain may stimulate CTGF is unclear; however, GLUT1 induction and/or increases in TGF-β may underlie the process [11,46]. These data suggest a potential amplification loop between GLUT1 and CTGF via TGF-β-dependent pathways, but the relationship remains to be defined.…”

“…At the level of the organism, all of the above processes are highly integrated. To address these events in vivo, several novel transgenic mouse models have helped to advance our understanding of the role of GLUT1 in the development of glomerulosclerosis and nephropathy [9,10,11]. …”

“…GLUT1-facilitated transport of glucose results in the activation of signaling cascades favoring glomerulosclerosis [8,10,11,12]. Thus, GLUT1 activity may be a regulator of the development of fibrosis in this disease.…”