Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.
BACKGROUND
Plasminogen activator inhibitor-1 (PAI-1) is increased in kidneys of humans and animals with diabetic nephropathy and is associated with extracellular matrix (ECM) accumulation. PAI-1 may promote ECM buildup by preventing plasmin and matrix metalloproteinase (MMP) activation. However, the importance and mechanism of PAI-1 action in the pathogenesis of diabetic nephropathy is unknown.


METHODS
We investigated the effect of streptozotocin (STZ)-induced diabetes in wild-type (PAI-1(+/+)) mice and mice null for PAI-1 (PAI-1(-/-)). After 1 month of diabetes, animals were placed in metabolic cages for 24-hour urine collection. Total RNA was isolated from kidney cortex for reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, and Western blots were quantitated from cortical protein. Primary mesangial cells were grown from Sprague-Dawley rats and used in signal transduction studies.


RESULTS
Urinary albumin excretion (UAE) in diabetic PAI-1(+/+) mice increased >threefold, but remained unchanged in PAI-1(-/-) mice. Transforming growth factor-beta (TGF-beta) and fibronectin message and protein levels were lower in diabetic PAI-1(-/-) vs. PAI-1(+/+) mice, suggesting that PAI-1 deficiency impaired TGF-beta expression despite diabetes. Indeed, recombinant PAI-1 directly stimulated TGF-beta message and protein via mitogen-activated protein kinase (MAPK) signal transduction in cultured mesangial cells. Urokinase plasminogen activator (uPA) inhibited this PAI-1 action in a dose-dependent manner. The inhibitory effect of antibody to uPA receptor (uPAR) on PAI-1-induced TGF-beta function suggested that uPAR mediated the cellular effect of PAI-1.


CONCLUSIONS
PAI-1 can regulate TGF-beta expression by binding to uPAR and activating the extracellular-regulated signal kinase (ERK)/MAPK pathway. Therefore, PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and renal ECM production and may be a therapeutic target in diabetic nephropathy.
Nicholas
Susanne B
SB
Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. sunicholas@mednet.ucla.edu
Aguiniga
Elsa
E
Ren
Yuelan
Y
Kim
Jason
J
Wong
Joyce
J
Govindarajan
Nalini
N
Noda
Masakuni
M
Wang
Wei
W
Kawano
Yasuko
Y
Collins
Alan
A
Hsueh
Willa A
WA
D000419:Albuminuria; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000502:physiology; D005920:Glomerular Mesangium / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017395:Plasminogen Activator Inhibitor 1