Renal endothelial protein C receptor expression and shedding during diabetic nephropathy.

UNLABELLED: Essentials Endothelial 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(-1) and 94.35 versus 140.6 ng mL(-1) , respectively). Accordingly, glomerular endothelial EPCR expression was markedly reduced in patients with DN, and this was associated with increased glomerular expression of ADAM-17 and ADAM-10. In vitro, EPCR shedding was induced by incubation of glomerular endothelium in high-glucose medium, and this shedding was suppressed by ADAM-17 inhibition or silencing, which led to improved vascular endothelial cadherin (VE-cadherin) expression and reduced mRNA expression of transforming growth factor (TGF)-ß. In addition, EPCR silencing led to minor effects on VE-cadherin but to a significant increase in TGF-ß mRNA expression. Conclusion Inhibition of ADAM-driven glomerular EPCR shedding restored the endothelial phenotype of glomerular endothelium, whereas EPCR silencing led to enhanced expression of TGF-ß, a marker of endothelial-mesenchymal transition. These findings demonstrate that EPCR shedding driven by ADAMs contributes to the worsening of DN.

Autonomic nervous control of the urinary bladder.

The autonomic nervous system plays an important role in the regulation of the urinary bladder function. Under physiological circumstances, noradrenaline, acting mainly on ß(3) -adrenoceptors in the detrusor and on α(1) (A) -adrenoceptors in the bladder outflow tract, promotes urine storage, whereas neuronally released acetylcholine acting mainly on M(3) receptors promotes bladder emptying. Under pathophysiological conditions, however, this system may change in several ways. Firstly, there may be plasticity at the levels of innervation and receptor expression and function. Secondly, non-neuronal acetylcholine synthesis and release from the urothelium may occur during the storage phase, leading to a concomitant exposure of detrusor smooth muscle, urothelium and afferent nerves to acetylcholine and noradrenaline. This can cause interactions between the adrenergic and cholinergic system, which have been studied mostly at the post-junctional smooth muscle level until now. The implications of such plasticity are being discussed.