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 inhibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischaemia followed by reperfusion. Renal function and tubular damage were analysed. RESULTS: Substantial JNK activation was evident in tubular epithelial cells in kidneys from 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.
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 inhibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischaemia followed by reperfusion. Renal function and tubular damage were analysed. RESULTS: Substantial JNK activation was evident in tubular epithelial cells in kidneys from 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.
Authors: Rongpei Lan; Hui Geng; Aaron J Polichnowski; Prajjal K Singha; Pothana Saikumar; Donald G McEwen; Karen A Griffin; Robert Koesters; Joel M Weinberg; Anil K Bidani; Wilhelm Kriz; Manjeri A Venkatachalam Journal: Am J Physiol Renal Physiol Date: 2012-02-01
Authors: Nancy-Ellen Haynes; Nathan R Scott; Li C Chen; Cheryl A Janson; Jia Kui Li; Christine M Lukacs; Aruna Railkar; Effie Tozzo; Toni Whittard; Nicholas F Brown; Adrian Wai-Hing Cheung Journal: ACS Med Chem Lett Date: 2012-08-08 Impact factor: 4.345
Authors: Hilary Cassidy; Robert Radford; Jennifer Slyne; Sein O'Connell; Craig Slattery; Michael P Ryan; Tara McMorrow Journal: J Signal Transduct Date: 2012-03-12