The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). There is an increasing recognition that age and CKD are risk factors for acute kidney injury (AKI) and that AKI most often develops as an acute-on-chronic injury. We have characterized an age- dependent model of CKD in our laboratory, which recapitulates the increased incidence and severity of acute kidney injury in the elderly. Our data demonstrate that aging is associated with loss of the N-cadherin/?-catenin complex;the N-cadherin/?-catenin complex is a target of nephrotoxic injury;and aging is associated with an increased susceptibility of tubular epithelial cells to acute injury. Based on these data, we hypothesize that the age-dependent loss of the N-cadherin/?-catenin complex increases susceptibility to nephrotoxicity.
Four Specific Aims have been designed to examine this hypothesis.
In Aim 1, the link between age-related loss of N-cadherin and susceptibility to mercuric chloride, a relevant environmental nephrotoxicant, will be examined in vivo. These studies will focus on the hypothesis that that both increased injury and diminished repair from nephrotoxic injury distinguish the aged kidneys.
In Aim 2, the direct relationship between N-cadherin loss and susceptibility to mercuric chloride will be examined in vitro using a number of molecular approaches, including overexpression and knockdown strategies.
Aim 3 will test the hypothesis loss of ?-catenin leads to disorganization of the actin cytoskeleton via increased Arp2/3 activity and decreased formin-1 mediated nucleation of linear actin cables, predisposing the aged kidney to nephrotoxic insult. Finally, in Aim 4, we will develop an inducible, proximal tubular epithelial-specific ?-catenin knockout mouse to our hypothesis in vivo. These studies will be the first data to link expression of the cadherin/catenin complex with response to injury;the link between loss of N-cadherin/?-catenin and injury has tremendous implications in our understanding of mechanisms of toxicity. In addition, these studies address a novel pathway underlying the increased susceptibility of the aging kidney to injury. Taken together, these studies represent a significant advance in attempts to manage the increasing burden of renal disease in the expanding geriatric population.

Public Health Relevance

Aging is associated with alterations in renal structure and function, which may predispose geriatric patients to acute kidney injury following exposure to nephrotoxicants. In these studies, we will examine changes that lead to the increased susceptibility of the aging kidney to injury.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Murthy, Mahadev
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University of Missouri-Columbia
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Grunz-Borgmann, Elizabeth A; Nichols, LaNita A; Wang, Xinhui et al. (2017) Twist2 Is Upregulated in Early Stages of Repair Following Acute Kidney Injury. Int J Mol Sci 18:
Grunz-Borgmann, Elizabeth A; Nichols, LaNita A; Wiedmeyer, Charles E et al. (2016) Structural equation modeling identifies markers of damage and function in the aging male Fischer 344 rat. Mech Ageing Dev 156:55-62
Wang, Xinhui; Parrish, Alan R (2015) Loss of ?(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells. Apoptosis 20:921-9
Grunz-Borgmann, Elizabeth; Mossine, Valeri; Fritsche, Kevin et al. (2015) Ashwagandha attenuates TNF-?- and LPS-induced NF-?B activation and CCL2 and CCL5 gene expression in NRK-52E cells. BMC Complement Altern Med 15:434
Wang, Xinhui; Grunz-Borgmann, Elizabeth A; Parrish, Alan R (2014) Loss of ?(E)-catenin potentiates cisplatin-induced nephrotoxicity via increasing apoptosis in renal tubular epithelial cells. Toxicol Sci 141:254-62
Trzeciakowski, Jerome P; Gardiner, Lesley; Parrish, Alan R (2014) Effects of environmental levels of cadmium, lead and mercury on human renal function evaluated by structural equation modeling. Toxicol Lett 228:34-41
Wang, Xinhui; Bonventre, Joseph V; Parrish, Alan R (2014) The aging kidney: increased susceptibility to nephrotoxicity. Int J Mol Sci 15:15358-76
Nichols, LaNita A; Slusarz, Anna; Grunz-Borgmann, Elizabeth A et al. (2014) ?(E)-catenin regulates BMP-7 expression and migration in renal epithelial cells. Am J Nephrol 39:409-17
Oelusarz, Anna; Nichols, Lanita A; Grunz-Borgmann, Elizabeth A et al. (2013) Overexpression of MMP-7 Increases Collagen 1A2 in the Aging Kidney. Physiol Rep 1:
Whaley-Connell, Adam T; Habibi, Javad; Nistala, Ravi et al. (2012) Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway. Am J Nephrol 35:90-100

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