Ex vivo transfer of the decorin gene into rat glomerulus via a mesangial cell vector suppressed extracellular matrix accumulation in experimental glomerulonephritis

Abstract Diabetic nephropathy (DN) is the common complications of diabetes mellitus, but the efficacy of available treatments for the prevention of DN is still unsatisfactory. In the present study, we aimed to explore the effect of Danggui buxue tang (DGT) on the proliferation of high glucose (HG)-induced mesangial cells and accumulation of extracellular matrix in mesangial cells. We found DGT up-regulated the expression of growth arrest specific transcript 5 (GAS5) and IκB kinase (IKK) dose-dependently in mouse mesangial cells (SV40 MES-13). We found DGT regulated the expression IKK and the activity of nuclear transcription factor-κB (NF-κB) via GAS5, and proved that long non-coding RNA (lncRNA) GAS5 was positively related with IKK. And we proved GAS5 regulated the expression of IKK and the activity of NF-κB. In addition, DGT inhibited the viability of MES-13 cells and extracellular matrix-related proteins (laminin (LN), fibronectin (FN) and collagen IV (Col IV)) via GAS5. Moreover, we proved GAS5 regulated the viability of SV40 MES-13 cells and extracellular matrix-related proteins through NF-κB pathway. DGT inhibited the proliferation of mesangial cells and accumulation of extracellular matrix via GAS5/NF-κB, therefore, DGT could be an effective treatment for the prevention of DN.

Download Full-text

Prevention of early glomerulopathy with tolrestat in the streptozotocin-induced diabetic rat

Biochemistry and Cell Biology ◽

10.1139/o96-038 ◽

1996 ◽

Vol 74 (3) ◽

pp. 355-362 ◽

Cited By ~ 27

Author(s):

Sandra M. Donnelly ◽

Jannet T. Huang ◽

Xiaopeng P. Zhou ◽

Catharine I. Whiteside

Keyword(s):

Extracellular Matrix ◽

Aldose Reductase ◽

Mesangial Cell ◽

Diabetic Rats ◽

Glomerular Hyperfiltration ◽

Diabetic Rat ◽

Glomerular Mesangial Cell ◽

Glomerular Permeability ◽

Functional Changes ◽

Matrix Accumulation

Hyperglycemia is of central importance in the pathogenesis of the complications of diabetes mellitus. Glucose activation of the polyol pathway may lead to renal arteriolar smooth muscle and glomerular mesangial cell hypocontractility. In the streptozotocin-induced diabetic rat, the effect of the aldose reductase inhibitor, tolrestat, in preventing glomerular hyperfiltration, renal hypertrophy, extracellular matrix accumulation, and mesangial cell hypocontractility was addressed. Streptozotocin-induced diabetic rats were followed for 12 weeks and half received tolrestat (25 mg/kg per day). Increased glomerular filtration rate was prevented by tolrestat (3.1 ± 0.3 vs. 1.8 ± 0.2 mL/min, diabetes vs. diabetes + tolrestat, p < 0.01), in part by reduction of the filtration fraction (0.39 ± 0.03 vs. 0.29 ± 0.01, diabetes vs. diabetes + tolrestat, p < 0.01). Tolrestat prevented the raised albumin excretion rates (3594 ± 1154 vs. 713 ± 161 mg/24 h, diabetes vs. diabetes + tolrestat, p < 0.01). Endothelin-1-induced contraction of isolated glomeruli was normal in tolrestat-treated diabetic animals compared with the hypocontractile diabetic glomeruli. Tolrestat prevented glomerular hypertrophy (1.86 ± 0.10 vs. 1.49 ± 0.03 μm2 × 105, diabetes vs. diabetes + tolrestat, p < 0.001) and attenuated the accumulation of basement-membrane-like material (50.2 ± 0.4% vs. 46.4 ± 0.8%, diabetes vs. diabetes + tolrestat, p < 0.001). Fractional mesangial expansion was unchanged in tolrestat-treated diabetic rats compared with untreated animals. Tolrestat prevents the functional changes of glomerular hyperfiltration, mesangial cell hypocontractility, and increased glomerular permeability to albumin. Polyol accumulation may have differential effects on glomerular growth and extracellular matrix accumulation in early diabetic nephropathy.Key words: aldose reductase, nephropathy, renal hemodynamics, renal morphometry, mesangium.

Download Full-text