Renal endothelial protein C receptor expression and shedding during diabetic nephropathy

Abstract

To cite this article: Lattenist L, Ochodnick y P, Ahdi M, Claessen N, Leemans JC, Satchell SC, Florquin S, Gerdes VE, Roelofs JJTH. Renal endothelial protein C receptor expression and shedding during diabetic nephropathy. J Thromb Haemost 2016; 14: 1171-82. EssentialsEndothelial protein C receptor (EPCR) promotes diabetic nephropathy (DN) outcome improvement. Renal expression and shedding of EPCR were measured in diabetic patients with or without DN. Inhibition of metalloproteinase-driven EPCR shedding restored glomerular endothelium phenotype. EPCR shedding through metalloproteinase ADAM17 contributes to the worsening of DN.Summary. Background: Diabetic nephropathy (DN) represents the leading cause of end-stage renal disease. The endothelial protein C receptor (EPCR) and its ligand (activated protein C) have been shown to ameliorate the phenotype of DN in mice. EPCR activity can be regulated by proteolytic cleavage involving ADAMs, yielding a soluble form of EPCR (sEPCR). Objective: To characterize the renal expression and shedding of EPCR during DN. Methods: EPCR levels were measured in plasma, urine and biopsy samples of diabetic patients with (n = 73) or without (n = 63) DN. ADAM-induced cleavage of EPCR was investigated in vitro with a human glomerular endothelium cell line. Results: DN patients showed higher plasma and urinary levels of sEPCR than diabetic controls (112.2 versus 135.2 ng mL À1 and 94.35 versus 140.6 ng mL À1

Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy

“…Human tubular epithelial HK-2 cells (ATCC, Manassas, VA) were grown to subconfluence in Dulbecco's modified Eagle's medium F12 medium (Invitrogen, Carlsbad, CA) (3:1) containing 10% fetal bovine serum, 2 mmol/L L-glutamine, 100 U/ mL penicillin, and 100 mg/mL streptomycin in a humidified 5% CO 2 atmosphere at 37 C. Cells were serum starved for 24 hours and then stimulated with 30 mmol/L of glucose (or 30 mmol/L of mannitol as osmotic control) and 10 ng/mL of transforming growth factor (TGF)-b to model the diabetic environment for 48 hours as described previously, 35 after which supernatant was collected and cells were harvested after washing with phosphate-buffered saline. Cell viability was assessed by the standard trypan blue exclusion test.…”

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

“…The common regulator of TNF-α and EGFR ligands, ADAM17, has been considered as a potential therapeutic target for chronic kidney diseases, particularly progressive fibrosis (15)(16)(17). In diseased Fcgr2b -/-kidneys, both ADAM17 and iRhom2 were upregulated, and iRhom2 was overexpressed in the kidneys of LN patients.…”

“…Although blocking ADAM17 could simultaneously shut down multiple pathogenic pathways and has been proposed for treating chronic kidney diseases not related to LN (15)(16)(17), there are substantial concerns about therapeutically targeting ADAM17, mainly because ADAM17 has an essential role in protecting the skin and intestinal barrier through activating the EGFR pathway (18,19). Indeed, mice lacking Adam17 die at birth due to defects in EGFR signaling, and individuals with ADAM17 mutation or those treated with EGFR inhibitors display skin and intestinal inflammation (20)(21)(22).…”

High Glucose Level Disturbs the Resveratrol-Evoked Curtailment of CX3CL1/CX3CR1 Signaling in Human Placental Circulation

“…Even after taking into account that LPS administration elicited higher CX3CL1 levels in the HG group compared to the NG group, the effectiveness of resveratrol (at 50 and 100  μ M) in decreasing CX3CL1 production (the percent reduction) by perfused placental lobules was significantly weakened in hyperglycemic conditions. It is worth mentioning that both hyperglycemia and inflammation influence proteolytic shedding on endothelial cells [44, 45]. Thus, further studies are needed to investigate whether observed changes in CX3CL1 levels are associated predominantly with the modulation of mRNA synthesis or proteolytic shedding.…”