Disruption of guanylyl cyclase-G protects against acute renal injury.
The membrane forms of guanylyl cyclase (GC) serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. Rat kidney contains mRNA for the GC-G isoform, but the role of this receptor in health and disease has not been characterized. It was found that mouse kidney also contains GC-G mRNA, and immunohistochemistry identified GC-G protein in the epithelial cells of the proximal tubule and collecting ducts. Six hours after ischemia-reperfusion (I/R) injury, GC-G mRNA and protein expression increased three-fold and remained upregulated at 24 h. For determination of whether GC-G mediates I/R injury, a mutant mouse with a targeted disruption of the GC-G gene (Gucy2g) was created. At baseline, no histologic abnormalities were observed in GC-G(-/-) mice. After I/R injury, elevations in serum creatinine and urea were attenuated in GC-G(-/-) mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation. Measures of inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin) and activation of NF-kappaB were lower in GC-G(-/-) mice compared with wild-type mice. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G(-/-) mice resulted in a dramatically higher mortality after renal I/R injury, further supporting a role for GC-G in mediating injury. In summary, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury.
Lin
Heng
H
Institute of Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, Taiwan.
Cheng
Ching-Feng
CF
Hou
Hsin-Han
HH
Lian
Wei-Shiung
WS
Chao
Ying-Chi
YC
Ciou
Yi-Yun
YY
Djoko
Bambang
B
Tsai
Ming-Tzu
MT
Cheng
Chien-Jui
CJ
Yang
Ruey-Bing
RB
D058186:Acute Kidney Injury / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics; D007668:Kidney / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics* / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology*
D015850:Interleukin-6; D016328:NF-kappa B; D019007:P-Selectin; D012333:RNA, Messenger; D009195:Peroxidase; D050705:Receptors, Guanylate Cyclase-Coupled; C514217:guanylyl cyclase-G, mouse