Abstract
A hallmark of aging-related organ deterioration is a dysregulated immune response characterized by pathologic leukocyte infiltration of affected tissues. Mechanisms and genes involved are as yet unknown. To identify genes associated with aging-related renal infiltration, we analyzed kidneys from aged mice (≥20 strains) for infiltrating leukocytes followed by Haplotype Association Mapping (HAM) analysis. Immunohistochemistry revealed CD45+ cell clusters (predominantly T and B cells) in perivascular areas coinciding with PNAd+ high endothelial venules and podoplanin+ lymph vessels indicative of tertiary lymphoid organs. Cumulative cluster size increased with age (analyzed at 6, 12 and 20 months). Based on the presence or absence of clusters in male and female mice at 20 months, HAM analysis revealed significant associations with loci on Chr1, Chr2, Chr8 and Chr14 in male mice, and with loci on Chr4, Chr7, Chr13 and Chr14 in female mice. Wisp2 (Chr2) showed the strongest association (P = 5.00×10−137) in male mice; Ctnnbip1 (P = 6.42×10−267) and Tnfrsf8 (P = 5.42×10−245) (both on Chr4) showed the strongest association in female mice. Both Wisp2 and Ctnnbip1 are part of the Wnt-signaling pathway and the encoded proteins were expressed within the tertiary lymphoid organs. In conclusion, this study revealed differential lymphocytic infiltration and tertiary lymphoid organ formation in aged mouse kidneys across different inbred mouse strains. HAM analysis identified candidate genes involved in the Wnt-signaling pathway that may be causally linked to tertiary lymphoid organ formation.
Highlights
As healthy individuals age most of them display a gradual decline in renal function as identified by diminished glomerular filtration rate [1]
To determine the composition of these cell clusters, sections were stained with the pan-leukocyte marker CD45, which is present on all hematopoietic cells, except erythrocytes and plasma cells
CD45 staining showed abundant expression in the renal perivascular cell clusters, indicating that these clusters were dominantly composed of leukocytes (Figure 1B)
Summary
As healthy individuals age most of them display a gradual decline in renal function as identified by diminished glomerular filtration rate [1]. It was previously shown that in a group of healthy subjects one third had no absolute decrease in renal function [3] suggesting that genetic predisposition for decline in renal function, or protection thereof, exists. Aging-related decline in renal function is characterized histopathologically by vascular, glomerular and tubulointerstitial scarring [4]. The process of progressive renal scarring with age is believed to result from repetitive clinical or silent insults of acute kidney injury, which is accompanied by local and systemic inflammatory processes. Attenuation of (aging-related) renal inflammation is expected to slow down the process of renal scarring and thereby functional decline
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