A plasminogen activator inhibitor type 1 mutant retards diabetic nephropathy in db/db mice by protecting podocytes.
A mutant non-inhibiting plasminogen activator inhibitor type 1 (PAI-1), termed PAI-1R, which reduces endogenous PAI-1 activity, has been shown to inhibit albuminuria and reduce glomerulosclerosis in experimental diabetes. The mechanism of the reduction of albuminuria is unclear. This study sought to determine whether the administration of PAI-1R protected podocytes from injury directly, thereby reducing albuminuria in the db/db mouse, a model of type 2 diabetes. Untreated uninephrectomized db/db mice developed significant mesangial matrix expansion and albuminuria at week 22 of age, associated with segmental podocyte foot-process effacement, reduction of renal nephrin, podocin and zonula occludin-1 production and induction of renal desmin and B7-1 generation. In contrast, treatment with PAI-1R at 0.5 mg (kg body weight)(-1) i.p., twice daily from week 20 to 22, reduced glomerular matrix accumulation, fibronectin and collagen production and albuminuria by 36, 62, 65 and 31%, respectively (P < 0.05), without affecting blood glucose level or body weight. Podocyte morphology and protein markers were also significantly attenuated by PAI-1R administration. Importantly, recombinant PAI-1 downregulated nephrin and zonula occludin-1 but increased desmin and B7-1 mRNA expression and protein production by podocytes in vitro, similar to the effects of transforming growth factor-β1. These observations provide evidence that PAI-1, in a manner similar to transforming growth factor-β1, directly induces podocyte injury, particularly in the setting of diabetes, where elevated PAI-1 may contribute to the progression of albuminuria. Reducing the increased PAI-1 activity by administration of PAI-1R, in fact, reduces podocyte injury, thereby reducing albuminuria. Therefore, PAI-1R provides an additional therapeutic effect in slowing the progression of diabetic nephropathy via the protection of podocytes.
Division of Nephrology & Hypertension, University of Utah School of Medicine, Salt Lake City, UT, USA.
Jiandong
J
Zhang
Division of Nephrology & Hypertension, University of Utah School of Medicine, Salt Lake City, UT, USA.
Chunyan
C
Gu
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Daniel A
DA
Lawrence
Division of Nephrology & Hypertension, University of Utah School of Medicine, Salt Lake City, UT, USA Medical Care Center, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
Alfred K
AK
Cheung
Division of Nephrology & Hypertension, University of Utah School of Medicine, Salt Lake City, UT, USA yufeng.huang@hsc.utah.edu.
Yufeng
Y
Huang
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D002478:Cells, Cultured; D003893:Desmin / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis
D018122:B7-1 Antigen; D003893:Desmin; D017395:Plasminogen Activator Inhibitor 1; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein