Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure.
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.
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA. Electronic address: Steven.haller@utoledo.edu.
Steven T
ST
Haller
Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Sivarajan
S
Kumarasamy
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
David A
DA
Folt
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Leah M
LM
Wuescher
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Stanislaw
S
Stepkowski
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Manish
M
Karamchandani
Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Harshal
H
Waghulde
Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Blair
B
Mell
Department of Pharmacology, Physiology, and Toxicology, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA.
Muhammad
M
Chaudhry
Department of Pharmacology, Physiology, and Toxicology, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA.
Kyle
K
Maxwell
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Siddhi
S
Upadhyaya
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Christopher A
CA
Drummond
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Jiang
J
Tian
Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Wanda E
WE
Filipiak
Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Thomas L
TL
Saunders
Department of Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA.
Joseph I
JI
Shapiro
Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Bina
B
Joe
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
Christopher J
CJ
Cooper
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics*; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D003404:Creatinine / Q000097:blood; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008213:Lymphocyte Activation; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020303:Rats, Inbred Dahl; D011922:Rats, Mutant Strains; D065667:Renal Elimination; D017673:Sodium Chloride, Dietary; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
D019013:CD40 Antigens; D017395:Plasminogen Activator Inhibitor 1; D017673:Sodium Chloride, Dietary; D003404:Creatinine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
CD40; hypertension; hypertensive renal disease; renal fibrosis; renal function
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