High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells

Abstract

Diabetic nephropathy is associated with mesangial ECM (extracellular matrix) accumulation. We have shown that AT-1R [Ang II (angiotensin II) type I receptor] signalling induces ECM proteins via transactivation of PI3K (phosphoinositide 3-kinase) in mesangial cells. In the present study, we examined the mechanisms underlying the effect of high ambient glucose on cell proliferation and ECM expansion in a mesangial context. High glucose induced increases in PI3K activity, proliferation and ECM accumulation in mesangial cells. These effects were abrogated by losartan, an AT-1R antagonist, but not by [Sar1,Thr8]-Ang II (Sar is sarcosine), an inactive analogue of Ang II, or by a neutralizing antibody against Ang I/II. Overexpression of a constitutively active PI3Kalpha or AT-1R alone was sufficient to induce similar changes by high glucose. In contrast, overexpression of an inactive AT-1R lowered the basal levels and rendered the cells non-responsive to high glucose. Moreover, cells overexpressing wild-type AT-1R had enhanced sensitivity to acute Ang II stimulation. These cells, however, did not respond to conditioned medium obtained from mesangial cells cultured in high glucose. We further demonstrated that iAng (intracellular Ang II) can be induced by high glucose but only under certain conditions. Efficient suppression of iAng by short hairpin RNA against angiotensinogen, however, did not affect high glucose-induced effects on MES-13 cells. These results suggest that high ambient glucose induces activation of AT-1R in an Ang II-independent manner to transactivate PI3K, resulting in proliferation and ECM accumulation in mesangial cells.

Evaluating Pharmacological Effects of Two Major Components of Shuangdan Oral Liquid: Role of Danshensu and Paeonol in Diabetic Nephropathy Rat

“…The frequent pathological characteristics of DN are the hypertrophy of glomerulus and kidney tubules, the broadening of mesangial area, the degeneration of vacuoles and the appearing of irregular shape epithelium in partial kidney tubules (Ayo et al ., 1990; Yano et al ., 2009), which may ultimately result in glomerular sclerosis and renal fibrosis. In this study, we observed that hypertrophy of glomerular and renal tubular was alleviated, basement membrane was not thickened, mesangial area was not obviously broadened, vacuoles degeneration was reduced in renal tubular epithelia in SDO, DSS, Pae, and DSS+Pae treatment groups.…”

Metformin Protects Cardiomyocyte from Doxorubicin Induced Cytotoxicity through an AMP-Activated Protein Kinase Dependent Signaling Pathway: An In Vitro Study

“…Whether Met, as a consequence of its modulated metabolism, influences cardiomyocyte survival remains unknown. We have previously reported a pro-survival/proliferation pathway in cardiomyocyte [24], [25] and renal mesangial cells [26], [27] involving G-protein coupled receptor (GPCR)-PKA-Src-receptor tyrosine kinase. The present study provides evidences that AMPK and PKA are activated sequentially following Met treatment.…”

Fluorofenidone Attenuates Diabetic Nephropathy and Kidney Fibrosis in <i>db/db</i> Mice

“…As in human diabetic nephropathy, the increased expression of several different genes encoding matrix proteins such as collagen and fibronectin contributes to their accumulation in glomerular matrices in diabetic db / db mice. It has been demonstrated that a high glucose concentration stimulates increased synthesis of ECM constituents in cultured mesangial cells [38,39] . In this study, AKF-PD treatment led to a significant reduction in mRNA expression of ␣ 1 (I)-and ␣ 1 (IV)-collagen, and fibronectin in the renal cortex of diabetic db / db mice.…”