Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice.
Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro, following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro, PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN.
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
Maaike
M
Waasdorp
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
JanWillem
J
Duitman
Department of Pathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
Sandrine
S
Florquin
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
C Arnold
CA
Spek
D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000172:deficiency*
D044463:Receptor, PAR-1