Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats

Background. Renal sympathetic nerve activity has important effects on renal function in chronic kidney disease. Recent studies indicated that beta agonists directly stimulate NAD(P)H oxidase in endothelial cells. Therefore, we investigated whether renal denervation protects renal function through an anti-oxidative effect. Methods. The right kidney was removed from Dahl salt-sensitive hypertensive rats. Two weeks later, the rats underwent either left renal denervation (Nx-RDNx; n = 10) or a sham operation (Nx-Sham; n = 10). After a further 6 weeks, kidney function and renal tissue were assessed. In this ex vivo study, using Results. After the Nx-RDNx or Nx-Sham surgery, urinary albumin excretion and the histologic glomerular sclerosis index were lower in the Nx-RDNx group than in the Nx-Sham group. Fluorescence staining for reactive oxygen species in isolated glomeruli was significantly weaker in the Nx-RDNx group. A lucigenin assay of NAD(P)H oxidase activity in isolated glomeruli indicated that renal denervation may have caused the reduction in reactive oxygen species through suppression of the activity of NAD(P)H oxidase. The levels of mRNA for NAD(P)H oxidase components and the levels of rac1 were higher in glomeruli from the Nx-Sham group than from the Nx-RDNx group. In this ex vivo study, although the NAD(P)H oxidase activity did not change with administration of either the α - or β 2-agonist, it increased with the β 1-agonist. Conclusions. Renal sympathetic denervation helps to pro-tect against glomerular sclerosis, possibly by suppressing NAD(P)H oxidase activity, thereby decreasing glomerular reactive oxygen species. Abstract Background. Ischaemia/reperfusion (I/R) is an important factor in delayed graft function in renal transplantation and is a determinant of long-term graft outcome. This study examined the role of c-Jun N-terminal kinase (JNK) signalling in human and experimental renal I/R injury. Methods. Biopsies obtained 15 – 20 min after reperfusion of human renal allografts were examined for JNK signalling by immunostaining for phospho-c-Jun. To examine the pathologic role of JNK signalling, a selective JNK in-hibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischae-mia followed by reperfusion. Renal function and tubular damage were analysed. deceased donors ( n = 30) which was less prominent in kidneys from live donors ( n = 7) (44.6 ± 24.8% vs 29.1 ± 20% p-c-Jun+, respectively; P < 0.05), whereas biopsies of thin basement membrane disease exhibited little, or no, p-c-Jun staining.The degree of p-c-Jun staining correlated with ischaemic time in deceased donor allografts, but not with graft function. Administration of CC-401 to rats prior to bilateral renal I/R prevented acute renal failure and largely prevented tubular damage, leucocyte infiltration and upregulation of pro-inflammatory molecules. However, delaying CC-401 treatment until 1 h after reperfusion (after the peak of JNK activation) had no protective effect. Conclusions. We have identified acute activation of the JNK signalling pathway following I/R in human kidney allografts. Experimental studies indicate that blockade of JNK signalling, commenced prior to this activation, can prevent acute tubular necrosis and renal dysfunction secondary to I/R injury.