TY - JOUR
T1 - Leptin stimulates type I collagen production in db/db mesangial cells
T2 - Glucose uptake and TGF-β type II receptor expression
AU - Han, Dong Cheol
AU - Isono, Motohide
AU - Chen, Sheldon
AU - Casaretto, Alberto
AU - Hong, Soon Won
AU - Wolf, Gunter
AU - Ziyadeh, Fuad N.
N1 - Funding Information:
This work was supported in part by the National Institutes of Health (grants DK-44513, DK-45191, and DK-54608 to F.N.Z.; training grant DK-07006, and Individual National Research Service Award to S.C.) and the Juvenile Diabetes Foundation International grant (to F.N.Z.) and fellowships (to M.I. and S.C.). D.C.H. was supported by the Korean Research Foundation, the Hyonam Kidney Laboratory, and Soon Chun Hyang University Hospital, Seoul, Korea. S.W.H. was supported by Yonsei University, Seoul, Korea. G.W. is a Heisenberg Scholar of the Deutsche Forschungsgemeinschaft.
PY - 2001
Y1 - 2001
N2 - Background. Serum leptin levels correlate with fat cell mass and are elevated in patients with massive obesity and type 2 diabetes mellitus, which are strong risk factors for the development of glomerulosclerosis. We have previously shown in cultured glomerular endothelial cells that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine transforming growth factor-β1 (TGF-β1). Although the effect of leptin on the hypothalamus to regulate energy homeostasis is well known, the effect of leptin on the kidney, and specifically on the glomerular mesangial cell, is unclear. Methods. The obese, diabetic db/db mouse, which lacks the functional full-length Ob-Rb leptin receptor, is a suitable model to assess the effects of hyperleptinemia on peripheral tissues that express other receptor isoforms. The effects of leptin on glucose uptake, the TGF-β system, and type I collagen production were evaluated in db/db mouse mesangial cells in culture. A phosphatidylinositol-3 kinase (PI-3K) inhibitor was used to assess the role of PI-3K in mediating the effects of leptin. Results. A short form of the leptin receptor (Ob-Ra), but not Ob-Rb, was present by reverse transcription-polymerase chain reaction in the kidney and mesangial cells of both nondiabetic db/m and diabetic db/db mice. In db/db mesangial cells, leptin increased 2-deoxy-D-glucose (2DOG) uptake dose dependently and stimulated gene expression of TGF-β type II receptor (TβRII) and α1(I) collagen, but not TGF-β1. Protein production of type I collagen (enzyme-linked immunosorbent assay) was also increased by leptin. Both leptin-stimulated 2DOG uptake and type I collagen production were suppressed by a PI-3K inhibitor, LY294002. Mesangial cells pretreated with leptin exhibited increased responsiveness to exogenous TGF-β1, as evidenced by a greater production of type I collagen protein in leptin-pretreated cells exposed to low-dose TGF-β1 (0.5 ng/mL). The addition of both TGF-β1 (2 ng/mL) and leptin (100 ng/mL) increased type I collagen production more than addition of either TGF-β1 or leptin alone. Conclusions. Leptin increases glucose uptake and type I collagen in db/db mesangial cells through a PI-3K-dependent pathway. We postulate that increased leptin levels may transmit a signal through the short-form leptin receptor to up-regulate TβRII and activate the intraglomerular TGF-β system, which may contribute to the glomerulosclerosis of obesity or type 2 diabetes.
AB - Background. Serum leptin levels correlate with fat cell mass and are elevated in patients with massive obesity and type 2 diabetes mellitus, which are strong risk factors for the development of glomerulosclerosis. We have previously shown in cultured glomerular endothelial cells that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine transforming growth factor-β1 (TGF-β1). Although the effect of leptin on the hypothalamus to regulate energy homeostasis is well known, the effect of leptin on the kidney, and specifically on the glomerular mesangial cell, is unclear. Methods. The obese, diabetic db/db mouse, which lacks the functional full-length Ob-Rb leptin receptor, is a suitable model to assess the effects of hyperleptinemia on peripheral tissues that express other receptor isoforms. The effects of leptin on glucose uptake, the TGF-β system, and type I collagen production were evaluated in db/db mouse mesangial cells in culture. A phosphatidylinositol-3 kinase (PI-3K) inhibitor was used to assess the role of PI-3K in mediating the effects of leptin. Results. A short form of the leptin receptor (Ob-Ra), but not Ob-Rb, was present by reverse transcription-polymerase chain reaction in the kidney and mesangial cells of both nondiabetic db/m and diabetic db/db mice. In db/db mesangial cells, leptin increased 2-deoxy-D-glucose (2DOG) uptake dose dependently and stimulated gene expression of TGF-β type II receptor (TβRII) and α1(I) collagen, but not TGF-β1. Protein production of type I collagen (enzyme-linked immunosorbent assay) was also increased by leptin. Both leptin-stimulated 2DOG uptake and type I collagen production were suppressed by a PI-3K inhibitor, LY294002. Mesangial cells pretreated with leptin exhibited increased responsiveness to exogenous TGF-β1, as evidenced by a greater production of type I collagen protein in leptin-pretreated cells exposed to low-dose TGF-β1 (0.5 ng/mL). The addition of both TGF-β1 (2 ng/mL) and leptin (100 ng/mL) increased type I collagen production more than addition of either TGF-β1 or leptin alone. Conclusions. Leptin increases glucose uptake and type I collagen in db/db mesangial cells through a PI-3K-dependent pathway. We postulate that increased leptin levels may transmit a signal through the short-form leptin receptor to up-regulate TβRII and activate the intraglomerular TGF-β system, which may contribute to the glomerulosclerosis of obesity or type 2 diabetes.
KW - Adipocyte-derived hormone
KW - Diabetic nephropathy
KW - Glomerulosclerosis
KW - Glomerulus
KW - Obesity
KW - Progressive renal disease
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U2 - 10.1046/j.1523-1755.2001.0590041315.x
DO - 10.1046/j.1523-1755.2001.0590041315.x
M3 - Article
C2 - 11260392
AN - SCOPUS:0035074193
SN - 0085-2538
VL - 59
SP - 1315
EP - 1323
JO - Kidney International
JF - Kidney International
IS - 4
ER -