Aging is associated with a loss of renal reserve, and increased sensitivity to either xenobiotic or physiologic insult. Given the critical role of the cadherin/catenin complex in establishing and maintaining the integrity and polarity of tubular epithelial cells, it was hypothesized that aging was associated with alterations in renal cadherin/catenin complexes. Histological assessment of aged (24 months) kidneys harvested from male Fischer 344 rats demonstrates mild degeneration of proximal tubules, multifocal chronic lymphocytic infiltration, moderate development of protein casts inside tubules, and tubular dilatation or degeneration. Western blot analysis revealed that N-cadherin protein expression is not constant over 24 months. N-cadherin expression increased from 4 to 9 months, with peak levels at 9 and 13 months. A decrease in expression was seen at 19 months and an almost complete loss of expression was seen at 24 months. In contrast, the expression of E- and Ksp-cadherin was constant over 24 months. A loss of alpha-catenin at was seen at 19 and 24 months in the absence of changes in beta-, gamma-, and p120-catenin. This pattern of N-cadherin expression (increase followed by decrease) was confirmed by real-time PCR analysis, which demonstrated a similar pattern as the Western blot, suggesting that the loss of N-cadherin protein was due to decreased gene expression. The loss of N-cadherin was specific for the kidney, as no changes in N-cadherin expression in the liver, brain, or testes were seen during aging. The conclusion that loss of N-cadherin expression is a critical component of the renal dysfunction associated with aging is supported by the finding that caloric restriction attenuates the loss of N-cadherin, as well as the finding that a significant loss of N-cadherin is seen in the kidneys of ZDF x SHHF rats, a genetic model of end-stage renal disease. Cadherin and catenin expression was further analyzed by immunofluorescence. A significant loss of staining of both N-cadherin and alpha-catenin was seen in the proximal tubules of rats at 24 months. Interestingly, this corresponded with delocalization of the alpha-1 subunit of the Na+K+-ATPase, i.e. aberrant staining on cell-cell borders and some indication of apical staining in proximal tubules. Taken together, these data suggest that aging is associated with decreased expression of N-cadherin and alpha-catenin and is associated with a loss of cell polarity.
"Acute kidney injury on a background of chronic kidney disease (CKD) is an important clinical problem (Singh et al. 2010; Chawla and Kimmel 2012). In rat models of CKD, including aging (Jung et al. 2004; Akintola et al. 2008), the ZDF-SHHR model of rapidly progressing chronic renal dysfunction (Jung et al. 2004), and the Ren2 transgenic rat model of fibrosis and proteinuria (Whaley- Connell et al. 2011, 2012), loss of N-cadherin and a-catenin expression has been demonstrated. It has been established by our laboratory (Jiang et al. 2004) and others (Leussink et al. 2001; Prozialeck et al. 2003; Nurnberger et al. 2010) that N-cadherin expression is reduced following acute injury. "
[Show abstract][Hide abstract] ABSTRACT: The aging kidney has a decreased ability to repair following acute kidney injury. Previous studies from our laboratory have demonstrated a loss in α-catenin expression in the aging rat kidney. We hypothesize that loss of α-catenin expression in tubular epithelial cells may induce changes that result in a decreased repair capacity. In these studies, we demonstrate that decreased α-catenin protein expression is detectable as early as 20 months of age in male Fischer 344 rats. Protein loss is also observed in aged nonhuman primate kidneys, suggesting that this is not a species-specific response. In an effort to elucidate alterations due to the loss of α-catenin, we generated NRK-52E cell lines with stable knockdown of α(E)-catenin (C2 cells). Interestingly, C2 cells had decreased expression of N-cadherin, decreased cell-cell adhesion, and increased monolayer permeability. C2 had deficits in wound repair, due to alterations in cell migration. Analysis of gene expression in the migrating control cells indicated that expression of N-cadherin and N-CAM was increased during repair. In migrating C2 cells, expression of N-CAM was also increased, but the expression of N-cadherin was not upregulated. Importantly, a blocking antibody against N-cadherin inhibited repair in NRK-52E cells, suggesting an important role in repair. Taken together, these data suggest that loss of α-catenin, and the subsequent downregulation of N-cadherin expression, is a mechanism underlying the decreased migration of tubular epithelial cells that contributes to the inability of the aging kidney to repair following injury.
"Alterations in the structure and function of the apical junctional complex and its associated proteins are associated with a variety of pathologic conditions including: glomerulonephritis (Nakopoulou et al., 2002), polycystic kidney disease (Barisoni et al., 1995;Rocco et al., 1992), renal ischemic injury (Bush et al., 2000;Molitoris & Marrs, 1999), aging (Jung et al., 2004) and renal carcinogenesis (Heicappell, 1999). In addition, there is a growing volume of evidence indicating that the apical junctional complex may be an important target of chemically-induced renal injury. "
[Show abstract][Hide abstract] ABSTRACT: Cell adhesion molecules are integral cell-membrane proteins that maintain cell-cell and cell-substrate adhesion and in some cases act as regulators of intracellular signaling cascades. In the kidney, cell adhesion molecules, such as the cadherins, the catenins, the zonula occludens protein-1 (ZO-1), occludin and the claudins are essential for maintaining the epithelial polarity and barrier integrity that are necessary for the normal absorption/excretion of fluid and solutes. A growing volume of evidence indicates that these cell adhesion molecules are important early targets for a variety of nephrotoxic substances including metals, drugs, and venom components. In addition, it is now widely appreciated that molecules, such as intracellular adhesion molecule-1 (ICAM-1), integrins, and selectins play important roles in the recruitment of leukocytes and inflammatory responses that are associated with nephrotoxic injury. This review summarizes the results of recent in vitro and in vivo studies indicating that these cell adhesion molecules may be primary molecular targets in many types of chemically-induced renal injury. Some of the specific agents that are discussed include cadmium (Cd), mercury (Hg), bismuth (Bi), cisplatin, aminoglycoside antibiotics, S-(1,2-dichlorovinyl)-l-cysteine (DCVC), and various venom toxins. This review also includes a discussion of the various mechanisms, by which these substances can affect cell adhesion molecules in the kidney.
"Overexpression of protein kinase C (PKC)-bI and PKC-d paralleled an increase in PKC activity in the proximal tubules of old Fisher rats, which may be responsible for hyperphosporylation of Na + /K + -ATPase and the diminished dopamine-induced inhibition of Na + /K + - ATPase activity (Asghar, Hussain & Lokhandwala, 2003). On the other hand, delocalization of a 1 -subunit Na + /K + -ATPase in the proximal tubules of aged Fisher rats (Jung et al., 2004) and increases in a 1 -subunit Na + /K + -ATPase abundance in aged Milan hypertensive rats (Ferrandi et al., 1996) have been reported. "
[Show abstract][Hide abstract] ABSTRACT: Na(+)/K(+)-ATPase plays a key role in the transport of Na(+) throughout the nephron, but ageing appears to be accompanied by changes in the regulation and localization of the pump. In the present study, we examined the effect of in vitro cell ageing on the transport of Na(+) and K(+) ions in opossum kidney (OK) cells in culture. Cells were aged by repeated passing, and Na(+)/K(+)-ATPase activity and K(+) conductance were evaluated using electrophysiological methods. Na(+)K(+)-ATPase alpha(1)- and beta(1)-subunit expression was quantified by Western blot techniques. Na(+)/H(+) exchanger activity, changes in membrane potential, cell viability, hydrogen peroxide production and cellular proliferation were determined using fluorimetric assays. In vitro cell ageing is accompanied by an increase in transepithelial Na(+) transport, which results from an increase in the number of Na(+)/K(+)-ATPase alpha(1)- and beta(1)-subunits, in the membrane. Increases in Na(+)/K(+)-ATPase activity were accompanied by increases in K(+) conductance as a result of functional coupling between Na(+)/K(+)-ATPase and basolateral K(+) channels. Cell depolarization induced by both KCl and ouabain was more pronounced in aged cells. No changes in Na(+)/H(+) exchanger activity were observed. H(2)O(2) production was increased in aged cells, but exposure for 5 days to 1 and 10 microM: of H(2)O(2) had no effect on Na(+)/K(+)-ATPase expression. Ouabain (100 nM: ) increased alpha(1)-subunit, but not beta(1)-subunit, Na(+)/K(+)-ATPase expression in aged cells only. These cells constitute an interesting model for the study of renal epithelial cell ageing.
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