Based on statistics from the US Census Bureau, in 2050, the number of Americans aged 65 and older is projected to be 88.5 million, more than double the population of 40.2 million in 2010. This older population carries a higher prevalence of both chronic kidney disease and acute kidney injury. Despite increasing interest in understanding the mechanisms of kidney aging and susceptibility to injury, there is a knowledge gap. One aspect of kidney biology that clearly changes with aging is regulation of the cell cycle. For example, p16INK4a is a gene that inhibits the cell cycle by controlling the activity of cyclin-dependent kinases, and levels of p16INK4A clearly rise in aged kidney. Since cell proliferation is crucial for kidney homeostasis and response to injury, this observation suggests that aged kidneys may be more susceptible to injury because they have decreased capacity to proliferate. We have recently identified a new cell cycle regulatory gene, Meis1, whose expression also rises both in response to injury and during aging. Meis1 is a known transcriptional activator of p16INK4a, and therefore in this proposal we hypothesize that Meis1 regulates cell senescence during kidney repair and during aging via up regulation of p16INK4a. To investigate this hypothesis, three specific aims are proposed.
The first aim i s to establish the expression pattern of Meis1 in the kidney at baseline and after acute kidney injury in young and aged mice.
In aim 2, we will try to define the role of Meis1 in renal tubular proliferation in vitro and in vivo afte injury.
In aim 3 will try to investigate whether Meis1 deletion ameliorates age-related fibrosis, loss of kidney function and susceptibility to AKI. Relevance: Given the rise in the aging population and the increase incidence of acute kidney injury and progression to chronic disease in this age group, the results of this study will help us to understand an important clinical condition whose incidence is rising in the US population. This in turn will lead to rational therapeutic strategies to prevent kidney injury among the elderly.
Acute kidney injury is much more common among the elderly, and the number of aged patients in the United States is rising rapidly. The purpose of this study is to explore the mechanisms that underlie this increased risk of acute kidney injury during aging, with a specific focus on cell cycle and cellular senescence. Understanding why aged kidneys are so susceptible to injury will point the way towards new treatments for this critically important clinical problem.
|Chang-Panesso, Monica; Kadyrov, Farid F; Machado, Flavia G et al. (2018) Meis1 is specifically upregulated in kidney myofibroblasts during aging and injury but is not required for kidney homeostasis or fibrotic response. Am J Physiol Renal Physiol 315:F275-F290|
|Chang-Panesso, Monica; Humphreys, Benjamin D (2015) CD248/Endosialin: A Novel Pericyte Target in Renal Fibrosis. Nephron 131:262-4|