TY - JOUR
T1 - Growth factor midkine is involved in the pathogenesis of diabetic nephropathy
AU - Kosugi, Tomoki
AU - Yuzawa, Yukio
AU - Sato, Waichi
AU - Kawai, Hanayo
AU - Matsuo, Seiichi
AU - Takei, Yoshifumi
AU - Muramatsu, Takashi
AU - Kadomatsu, Kenji
N1 - Funding Information:
Supported by grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan ( 14580647 to K.K.; 15390103 to T.M.; 15590849 to Y.Y. ).
PY - 2006/1
Y1 - 2006/1
N2 - Diabetic nephropathy is a life-threatening disease associated with diabetes mellitus. Longstanding hyperglycemia induces pathological reactions of glomerular mesangial cells, such as overproduction of extracellular matrix, which finally lead to nephropathy. However, the mechanisms underlying its pathogenesis have not been completely elucidated. Using the Streptozotocin- induced model of diabetes, we report that mice deficient in the growth factor midkine (Mdk-/-) exhibited strikingly milder nephropathy than Mdk +/+ mice, even though both mice showed similar extents of hyperglycemia after Streptozotocin injection. Midkine expression was induced in the glomerular mesangium of Mdk +/+ mice with diabetic nephropathy and in primary cultured mesangial cells exposed to high glucose. Mdk -/- mesangial cells exhibited reduced phosphorylation of protein kinase C and extracellular signal-regulated kinase as well as reduced production of transforming growth factor-β1 on high glucose loading. Addition of exogenous midkine restored extracellular signal-regulated kinase phosphorylation in Mdk -/- cells under high glucose conditions, whereas a midkine antisense oligodeoxynucleotide suppressed midkine in Mdk +/+ cells. Therefore, this study identifies midkine as a key molecule in diabetic nephropathy and suggests that midkine accelerates the intracellular signaling network evoked by hyperglycemia in nephropathy.
AB - Diabetic nephropathy is a life-threatening disease associated with diabetes mellitus. Longstanding hyperglycemia induces pathological reactions of glomerular mesangial cells, such as overproduction of extracellular matrix, which finally lead to nephropathy. However, the mechanisms underlying its pathogenesis have not been completely elucidated. Using the Streptozotocin- induced model of diabetes, we report that mice deficient in the growth factor midkine (Mdk-/-) exhibited strikingly milder nephropathy than Mdk +/+ mice, even though both mice showed similar extents of hyperglycemia after Streptozotocin injection. Midkine expression was induced in the glomerular mesangium of Mdk +/+ mice with diabetic nephropathy and in primary cultured mesangial cells exposed to high glucose. Mdk -/- mesangial cells exhibited reduced phosphorylation of protein kinase C and extracellular signal-regulated kinase as well as reduced production of transforming growth factor-β1 on high glucose loading. Addition of exogenous midkine restored extracellular signal-regulated kinase phosphorylation in Mdk -/- cells under high glucose conditions, whereas a midkine antisense oligodeoxynucleotide suppressed midkine in Mdk +/+ cells. Therefore, this study identifies midkine as a key molecule in diabetic nephropathy and suggests that midkine accelerates the intracellular signaling network evoked by hyperglycemia in nephropathy.
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U2 - 10.2353/ajpath.2006.050488
DO - 10.2353/ajpath.2006.050488
M3 - Article
C2 - 16400005
AN - SCOPUS:30344443053
SN - 0002-9440
VL - 168
SP - 9
EP - 19
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -