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A plasminogen activator inhibitor type 1 mutant retards diabetic nephropathy in db / db mice by protecting podocytes
Author(s) -
Zhang Jiandong,
Gu Chunyan,
Lawrence Daniel A.,
Cheung Alfred K.,
Huang Yufeng
Publication year - 2014
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2013.077610
Subject(s) - nephrin , albuminuria , endocrinology , medicine , podocyte , podocin , diabetic nephropathy , plasminogen activator , plasminogen activator inhibitor 1 , biology , diabetes mellitus , kidney , proteinuria
New FindingsWhat is the central question of this study? The mechanism by which PAI‐1R reduces proteinuria has not been previously explored.What is the main finding and its importance? Using cultured podocytes and diabetic db / db mice, we show that, similar to the effects of transforming growth factor‐β1, PAI‐1 directly injures podocytes. Reducing the increased PAI‐1 activity by PAI‐1R in diabetic db / db mice, in fact, reduces podocyte injury, thereby reducing albuminuria. Therefore, PAI‐1R may provide an additional therapeutic effect in slowing progression of diabetic nephropathy by maintaining podocyte integrity.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.