Age (>60yrs) is associated with increased mortality after acute kidney injury (AKI) with survivors being left with chronic kidney disease and on dialysis costing $10 billion per year. Components of the underlying mechanism that lead from AKI to failure to recover kidney function and CKD have been identified using animal models including ischemia-reperfusion injury. Increased apoptosis, inflammation and deposition of extracellular matrix result in renal fibrosis and renal failure. Persistent activation of pro-inflammatory and pro-fibrotic signals are important mediators of this process. It is not understood well why older individuals are at increased risk for delayed, incomplete or absent recovery after AKI. The NF-kappaB pathway has been identified as an activator of age-related transcriptional changes in human and rodents and is thought to mediate development of both GS and TIF following tissue injury. Micro-RNAs have recently been found to play an important role in coordinating the apoptotic and pro-fibrotic response to NF-kappaB activation. microRNAs (miRs), are small RNA molecules (19-22 nucleotides long) that coordinate pathways of gene expression via partial complementary to target mRNAs. They are a particularly attractive avenue for investigation because of their therapeutic potential as long-lasting drugs that can modulate molecular pathways. Our preliminary data show delayed recovery from ischemia-reperfusion injury in young adult miR-21 knockout mice. In addition, miR-21 inhibits apoptosis in cultured renal epithelial cells. Because we detected increasing miR-21 expression in the kidney during aging, we hypothesize that this increased miR-21 expression plays a protective role that prevents activation of the apoptotic and pro-fibrotic pathway activation in response to injury through inhibiting components of the NF-kappaB pathway and crosstalk with p53 and TGF-beta signaling. We propose to determine whether loss of miR-21 alters the response to ischemia-reperfusion injury associated with aging by examining renal function, histologic changes and cellular mechanisms known to mediate IR injury in miR-21 null mice. Furthermore, we will define the underlying mechanism of age-associated changes and its regulation by miR-21 in the renal response to IR injury using genome-wide expression profiling and a systems biology approach to compare patterns of transcriptional network structures. We expect that old mice lacking miR-21 will exhibit increased susceptibility to ischemia-reperfusion than young mice and their wildtype litter-mates with an intact miR-21 regulatory machinery. Demonstration of this protective relationship for miR-21 will open up the possibility that this micro-RNA could be used therapeutically.

Public Health Relevance

Patients of increased age (above 60 years) have a higher risk to have persistent decreased kidney function (Chronic Kidney Disease) or complete failure of the kidneys if their kidneys are damaged acutely costing the society over $10 billion per year. In addition, patients with acute injury of the kidneys are more likely to die. Because the number of older adults continues to rise, it is important to understand what causes the risk of an unfavorable outcome to rise with age. Our knowledge about the underlying mechanisms that are responsible for these differences are very limited and this is one reason why neither markers for early detection nor therapeutic interventions are available to patients. To improve the outcome of this potentially devastating disease, we have explored the role of newly discovered RNA molecules (microRNAs) in development and recovery from kidney injury. These molecules are in particular interesting because they could be used as new drugs. One of these microRNAs (miR-21) appears to prevent cell death and thereby protect the kidney in young mice. Therefore, we plan to study older mice and determine whether loss of miR-21 leads to worse outcome meaning persistent chronic damage to the kidneys or death after an acute injury to the kidneys. If these studies support a protective role of miR-21, future project will explore ways to increase miR-21 levels to prevent and treat acute kidney injury and thereby open new options for patient with acute kidney injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG040651-02
Application #
8306690
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
Program Officer
Murthy, Mahadev
Project Start
2011-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$77,750
Indirect Cost
$27,750
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109