Critical role for osteopontin in diabetic nephropathy.
The profibrotic adhesion molecule, osteopontin (OPN), is upregulated in kidneys of humans and mice with diabetes. The thiazolidinedione (TZD) insulin sensitizers decrease albuminuria in diabetic nephropathy (DN) and reduce OPN expression in vascular and cardiac tissue. To examine whether OPN is a critical mediator of DN we treated db/db mice with insulin, rosiglitazone, or pioglitazone to achieve similar fasting plasma glucose levels. The urine albumin-to-creatinine ratio and glomerular OPN expression were increased in diabetic mice, but both were reduced by the TZDs more than by insulin. We administered streptozotocin to OPN-null and OPN-wild-type mice, and OPN-null mice were bred into both type 1 (Ins2(akita/+)) and 2 (db/db) diabetic mice. In each case, OPN deletion decreased albuminuria, mesangial area, and glomerular collagen IV, fibronectin and transforming growth factor (TGF)-beta in the diabetic mice compared with their respective controls. In cultured mouse mesangial cells, TZDs but not insulin decreased angiotensin II-induced OPN expression, while recombinant OPN upregulated TGF-beta, ERK/MAPK, and JNK/MAPK signaling. These studies show that OPN expression in DN mouse models enhances glomerular damage, likely through the expression of TGF-beta, while its deletion protects against disease progression, suggesting that OPN might serve as a therapeutic target.
Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Susanne B
SB
Nicholas
Joey
J
Liu
Jason
J
Kim
Yuelan
Y
Ren
Alan R
AR
Collins
Lam
L
Nguyen
Willa A
WA
Hsueh
D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024141:Collagen Type IV; D005353:Fibronectins; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D000804:Angiotensin II