Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure

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• 作者：Steven T. Haller¹ ; ² ; ^{Steven.haller@utoledo.edu} ; Sivarajan Kumarasamy² ; ³ ; David A. Folt¹ ; Leah M. Wuescher⁴ ; Stanislaw Stepkowski⁴ ; Manish Karamchandani¹ ; ² ; Harshal Waghulde² ; ³ ; Blair Mell² ; ³ ; Muhammad Chaudhry⁵ ; Kyle Maxwell⁵ ; Siddhi Upadhyaya¹ ; Christopher A. Drummond¹ ; ² ; Jiang Tian¹ ; ² ; Wanda E. Filipiak⁶ ; Thomas L. Saunders⁶ ; Joseph I. Shapiro⁷ ; Bina Joe² ; ³ ; Christopher J. Cooper¹ ; ²
• 关键词：CD40 ; hypertensive renal disease ; hypertension ; renal fibrosis ; renal function
• 刊名：Kidney International
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：91
• 期：2
• 页码：365-374
• 全文大小：2602 K
• 卷排序：91

文摘

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 Cd40 in the development of hypertensive renal disease. The Cd40 gene 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 Cd40 mutants 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 Cd40 locus. Furthermore, the Cd40 mutants 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 Cd40 mutant 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.