Abstract
Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.5 CD40 ASO reduced CD40 mRNA and protein levels 75–90% in the kidney. CD40 ASO treatment mitigated functional, transcriptional, and pathological endpoints of doxorubicin-induced nephropathy. Experiments using an activating CD40 antibody revealed CD40 is primed in kidneys following doxorubicin injury or unilateral ureter obstruction and CD40 ASO treatment blunted CD40-dependent renal inflammation. Suborgan fractionation and imaging studies demonstrated CD40 in glomeruli before and after doxorubicin administration that becomes highly enriched within interstitial and glomerular foci following CD40 activation. Such foci were also sites of ASO distribution and activity and may be predominately comprised from myeloid cells as bone marrow CD40 deficiency sharply attenuated CD40 antibody responses. These studies suggest an important role of interstitial renal and/or glomerular CD40 to augment kidney injury and inflammation and demonstrate that ASO treatment could be an effective therapy in such disorders.
Highlights
13% of the US population suffers from chronic kidney disease and the prevalence of this condition is expected to rise.[1,2] Glomerulonephritis is a common manifestation of chronic kidney disease and is associated with chronic interstitial inflammation and fibrosis.[3]
The experiments described were conducted to (i) identify renal sites susceptible to CD40 activation, (ii) determine whether antisense inhibition of CD40 could ameliorate disease in a mouse model of glomerular injury, (iii) test the hypothesis that CD40 is primed in kidneys with preexisting injury, and (iv) determine if CD40-dependent renal inflammation could be abrogated with CD40 antisense oligonucleotides (ASOs) treatment
Our results demonstrate that CD40 ASO treatment resulted in a 75–90% reduction of renal CD40 across several models of kidney injury
Summary
13% of the US population suffers from chronic kidney disease and the prevalence of this condition is expected to rise.[1,2] Glomerulonephritis is a common manifestation of chronic kidney disease and is associated with chronic interstitial inflammation and fibrosis.[3]. An appreciation of this pathway in chronic inflammatory diseases has contributed to a much wider understanding of CD40 biology.[5,6,7,8,9,10] The broad cellular expression of CD40 on nonhematopoietic cells within the kidney like fibroblasts, endothelium, and epithelial cells underscores its role in the regulation of both adaptive and innate immunity in various disease states.[11,12,13,14]
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