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

Autor: Leah M. Wuescher, Manish Karamchandani, Sivarajan Kumarasamy, Siddhi Upadhyaya, Thomas L. Saunders, Joseph I. Shapiro, Stanislaw M. Stepkowski, Steven T. Haller, Jiang Tian, Kyle Maxwell, Christopher J. Cooper, David A Folt, Harshal Waghulde, Bina Joe, Wanda E. Filipiak, Christopher A. Drummond, Blair Mell, Muhammad A. Chaudhry
Rok vydání: 2015
Předmět:
0301 basic medicine
medicine.medical_specialty
Time Factors
T-Lymphocytes
Renal function
Blood Pressure
030204 cardiovascular system & hematology
Kidney
Lymphocyte Activation
Rats
Mutant Strains
Article
Excretion
03 medical and health sciences
0302 clinical medicine
Cell Movement
Hypertensive Nephropathy
Internal medicine
Plasminogen Activator Inhibitor 1
medicine
Renal fibrosis
Animals
Genetic Predisposition to Disease
CD40 Antigens
Phosphorylation
Sodium Chloride
Dietary
B-Lymphocytes
Proteinuria
Rats
Inbred Dahl
business.industry
Diet
Sodium-Restricted
medicine.disease
Fibrosis
Disease Models
Animal
Renal Elimination
030104 developmental biology
Blood pressure
Endocrinology
Phenotype
src-Family Kinases
Nephrology
Creatinine
Hypertension
Mutation
Ischemic Nephropathy
Kidney Diseases
medicine.symptom
business
Kidney disease
Zdroj: Kidney international. 91(2)
ISSN: 1523-1755
Popis: 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.
Databáze: OpenAIRE
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