Leptin stimulates type I collagen production in db/db mesangial cells: Glucose uptake and TGF-β type II receptor expression

Han, Dong Cheol; Isono, Motohide; Chen, Sheldon; Casaretto, Alberto; Hong, Soon Won; Wolf, Günter; Ziyadeh, Fuad N.

doi:10.1046/j.1523-1755.2001.0590041315.x

Cited by 131 publications

(96 citation statements)

References 41 publications

(6 reference statements)

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“…The db/db mouse, which lacks signalling through the leptin receptor, is an excellent model of type 2 diabetes because it develops hyperphagia, obesity, hyperleptinaemia and overt hyperglycaemia [40]. In this study, db/db mice, with or without resveratrol treatment, ate about twice the amount eaten by the db/m mice.…”

Section: Discussionmentioning

confidence: 82%

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

et al. 2012

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Aims/hypothesis Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. Methods Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. Results The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/ lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. Conclusions/interpretation The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

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Section: Discussionmentioning

confidence: 82%

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

et al. 2012

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“…Leptin is a potential progression promoter 45 and enhances the effect of TGF-b. 46,47 The action of leptin in some cells is mediated by norepinephrine, a leptin-inducible neurotransmitter. Against this background, it is of interest that both ACE-i and D3-RA reduced leptin concentrations in the present study.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Gross

Koch

Mühlbauer

et al. 2006

Laboratory Investigation

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Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensinconverting enzyme inhibitor (ACE-i), or D3-RA þ ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (Po0.05) in untreated diabetic animals (1.6270.3) compared to nondiabetic controls (0.470.2) and the treatment groups (D3-RA: 0.3170.12; ACE-i: 0.2970.1; combination treatment: 0.1270.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102719) compared to nondiabetic controls (31712) and the treatment groups (D3-RA: 44715; ACE-i: 41713; combination treatment: 1578). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.

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“…It has been shown that leptin may act directly as a renal growth and fibrogenic factor, stimulating proliferation of glomerular endothelial cells and collagen production in mesangial cells. 13,21 The fact that the latter effect occurred in db/db mouse mesangial cells, which lack the functional long form of the leptin receptor (ob.R L ), and that abundant short leptin receptor isoform (ob.R s ) is detected in abundance in kidney tissue 22 suggests that the direct effects of leptin on the kidney are mediated via ob.R s . Leptin has also been shown to directly increase diuresis and natriuresis without altering blood pressure or potassium excretion.…”

Section: Discussionmentioning

confidence: 99%

Leptin induces rat glomerular mesangial cell hypertrophy, but does not regulate hyperplasia or apoptosis

2005

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OBJECTIVE: There is an increased incidence of renal glomerulosclerosis in obese individuals. One of the major structural changes observed in nephropathy is the increase in kidney size, which may occur due to hypertrophy or changes in the rate of hyperplasia or apoptosis. Here we investigated whether leptin, the product of the obese (ob) gene which is found at high plasma levels in obese and diabetic individuals, alters any of these parameters. RESULTS: We show that leptin increased hypertrophy of these cells. This was indicated by an approximately 33% increase in cell size and 40% increase in leucine incorporation. Furthermore, we show that the hypertrophic effect of leptin was mediated via PI 3-kinase and ERK1/2 by using the inhibitors LY294002 and PD98059, respectively. We also confirm that leptin activates both PI 3-kinase and ERK1/2 in these cells. We show that hyperplasia was not affected by leptin by measuring rat glomerular mesangial cell number and by assessing bromodeoxyuridine uptake. Leptin also did not alter caspase 3-like activity under control conditions or upon induction of apoptosis by ultraviolet light, suggesting that apoptosis was not regulated by leptin in these cells. CONCLUSION: Our results show that leptin induced glomerular mesangial cell hypertrophy via PI 3-kinase and ERK1/2, and that hyperplasia and apoptosis were not altered by leptin. The hypertrophic effect of leptin may play a role in the pathophysiology of nephropathy associated with obesity.

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Leptin stimulates type I collagen production in db/db mesangial cells: Glucose uptake and TGF-β type II receptor expression

Cited by 131 publications

References 41 publications

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Leptin induces rat glomerular mesangial cell hypertrophy, but does not regulate hyperplasia or apoptosis

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