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

Abstract

<p class="first" id="P2">High blood pressure is a common cause of chronic kidney disease. Since 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 <i>Cd40</i> in the development of hypertensive renal disease. The <i>Cd40</i> 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 <i>Cd40</i> mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24hours vs. 103.7 ± 4.3 mg/24hours) and plasma creatinine (0.36 ± 0.05 mg/dL vs. 1.15 ± 0.19 mg/dL), with significantly higher creatinine clearance compared to the control S rats (3.04 ± 0.48 ml/minute vs. 0.93 ± 0.15 ml/minute) indicating renoprotection was conferred by mutation of the <i>Cd40</i> locus. Furthermore, the <i>Cd40</i> 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 <i>Cd40</i> 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. </p>