학술논문
Targeted disruption of Cd40in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure
Document Type
Article
Author
Haller, Steven T.; Kumarasamy, Sivarajan; Folt, David A.; Wuescher, Leah M.; Stepkowski, Stanislaw; Karamchandani, Manish; Waghulde, Harshal; Mell, Blair; Chaudhry, Muhammad; Maxwell, Kyle; Upadhyaya, Siddhi; Drummond, Christopher A.; Tian, Jiang; Filipiak, Wanda E.; Saunders, Thomas L.; Shapiro, Joseph I.; Joe, Bina; Cooper, Christopher J.
Source
Kidney International; February 2017, Vol. 91 Issue: 2 p365-374, 10p
Subject
Language
ISSN
00852538; 15231755
Abstract
High blood pressure is a common cause of chronic kidney disease. Because CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40in the development of hypertensive renal disease. The Cd40gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology. These rats were then given low (0.3%) and high (2%) salt diets and compared. The resultant Cd40mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24 h vs. 103.7 ± 4.3 mg/24 h) and plasma creatinine (0.36 ± 0.05 mg/dl vs. 1.15 ± 0.19 mg/dl), with significantly higher creatinine clearance compared with the control S rats (3.04 ± 0.48 ml/min vs. 0.93 ± 0.15 ml/min), indicating renoprotection was conferred by mutation of the Cd40locus. Furthermore, the Cd40mutants had a significant attenuation in renal fibrosis, which persisted on the high salt diet. However, there was no difference in systolic blood pressure between the control and Cd40mutant rats. Thus, these data serve as the first evidence for a direct link between Cd40 and hypertensive nephropathy. Hence, renal fibrosis is one of the underlying mechanisms by which Cd40 plays a crucial role in the development of hypertensive renal disease.