Abstract
CD44 contributes to the activation of glomerular parietal epithelial cells (PECs). Although CD44 expression is higher in PECs of healthy aged mice, the biological role of CD44 in PECs in this context remains unclear. Accordingly, young (4 months) and aged (24 months) CD44−/− mice were compared to age‐matched CD44+/+ mice, both aged in a nonstressed environment. Parietal epithelial cell densities were similar in both young and aged CD44+/+ and CD44−/− mice. Phosphorylated ERK 1/2 (pERK) was higher in aged CD44+/+ mice. Vimentin and α‐SMA, markers of changes to the epithelial cell phenotype, were present in PECs in aged CD44+/+ mice, but absent in aged CD44−/− mice in both outer cortical (OC) and juxtamedullary (JM) glomeruli. Because age‐related glomerular hypertrophy was lower in CD44−/− mice, mTOR activation was assessed by phospho‐S6 ribosomal protein (pS6RP) staining. Parietal epithelial cells and glomerular tuft staining for pS6RP was lower in aged CD44−/− mice compared to aged CD44+/+ mice. Podocyte density was higher in aged CD44−/− mice in both OC and JM glomeruli. These changes were accompanied by segmental and global glomerulosclerosis in aged CD44+/+ mice, but absent in aged CD44−/− mice. These results show that the increase in CD44 in PECs in aged kidneys contributes to several changes to the glomerulus during healthy aging in mice, and may involve ERK and mTOR activation.
Highlights
A better understanding of kidney aging is necessary as our population is living longer, and because the severity of kidney disease increases with advancing age (Epstein, 1996; Glassock & Rule, 2012; Hommos, Glassock, & Rule, 2017; Sweetwyne et al, 2017; Wiggins, 2012)
We have reported that increased CD44 expression in parietal epithelial cells (PECs) in experimental FSGS colocalizes with phosphorylated ERK 1/2 (Eng et al, 2015; Roeder et al, 2017)
Compared with aged CD44+/+ mice, Phosphorylated ERK 1/2 (pERK) staining was lower in PECs in JM glomeruli of aged CD44−/− mice (p < .0001), with no differences in pERK staining in outer cortical (OC) glomeruli (p = .42). These results show that pERK increased in PECs in both aged CD44+/+ and CD44−/− mice but was lower in aged CD44−/− mice, compared to aged CD44+/+ mice
Summary
A better understanding of kidney aging is necessary as our population is living longer, and because the severity of kidney disease increases with advancing age (Epstein, 1996; Glassock & Rule, 2012; Hommos, Glassock, & Rule, 2017; Sweetwyne et al, 2017; Wiggins, 2012). We have reported several changes in PECs in aged mouse kidneys, including increased CD44 expression in JM glomeruli compared with OC glomeruli, increased staining for epithelial–mesenchymal transition (EMT) markers vimentin and α-SMA, and the accumulation of the extracellular matrix proteins collagen type IV and heparin sulfate proteoglycan (Roeder et al, 2015). Several of these changes, including CD44 expression in PECs, can be limited or even prevented, by giving aged mice the mitochondrial stabilizer SS-31 (Sweetwyne et al, 2017). The purpose of the studies described was to better define the role of CD44 in PECs in the healthy aged kidney, by studying CD44−/− mice at an advanced age
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