Ischemia reperfusion (IR) induced renal injury causes acute renal failure and is associated with high morbidity and mortality rates. The cellular mechanisms underlying IR renal injury are not known. Meprins, metalloproteases that are abundantly expressed in the brush border membranes (BBM) of proximal kidney tubules, have been implicated in the pathology of IR. Mice strains with lower levels of meprins develop less renal injury when subjected to IR. Meprin inhibitors and targeted disruption of the meprin gene both protect mice from IR induced renal injury. We recently demonstrated that meprins cleave actin and villin, the key components of the proximal tubule cell cytoskeleton, suggesting that the observed renal injury is in part due to degradation of cytoskeletal proteins. Meprin B also cleaves the catalytic subunit of protein kinase A (PKA), a protein that modulates many cellular signaling pathways. OS-9, a protein involved in the hypoxia response, has been shown to interact with the carboxyl-terminal tail of meprin. However, it is not known if OS-9 is a meprin substrate, and whether interaction between OS-9 and meprin plays a role in the pathology of IR induced renal injury. The broad long term goal of this project is to elucidate the cellular mechanisms responsible for IR induced kidney injury, and facilitate development of therapies to prevent IR associated renal failure. The central hypothesis is that meprins play a key role in the injuries observed in renal IR. This is in part due to cleavage of cytoskeletal proteins (such as villin and actin), proteins present in tight junction complexes, and extracellular matrix (ECM) proteins. Meprins may also play an indirect role by cleaving proteins that modulate specific signaling pathways (such as PKA and OS-9) and thus impacting expression of genes driven by these pathways. The proposed studies will use meprin knockout mice and proteomic approaches to identify meprin associated proteins that play a role in IR and elucidate underlying cellular mechanisms. The central hypothesis will be tested by pursuing the following three specific aims: (i) to identify meprin-associated proteins that play a role in IR induced renal injuy, (ii) to determine the role of meprins in cytoskeletal remodeling associated with IR induced renal injury, (iii) to determine if interactions between meprins and cell signaling molecules play a role in IR induced kidney injury. Results from the proposed studies are expected to have an important positive impact because elucidating the mechanisms underlying IR induced renal injury will facilitate development of therapies for preventing acute renal failure due to IR.

Public Health Relevance

Ischemia-reperfusion (IR) causes kidney injury which leads to acute renal failure. The cellular mechanisms underlying IR renal injury are not known. There is increasing evidence that meprins contribute to renal injury in IR. The in vivo kidney meprin targets have not been identified. Data from the proposed studies will identify kidney meprin substrates that play a role in the pathology of IR, and provide insights into underlying cellular mechanisms. This will ultimately facilitate development of pharmacological agents for preventing kidney failure associated with IR renal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM102049-03
Application #
8685281
Study Section
Special Emphasis Panel (ZGM1-MBRS-Y (SC))
Program Officer
Krasnewich, Donna M
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$106,875
Indirect Cost
$31,875
Name
North Carolina Agri & Tech State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
071576482
City
Greensboro
State
NC
Country
United States
Zip Code
27411
Cao, Lei; Sedighi, Rashin; Boston, Ava et al. (2018) Undiagnosed Kidney Injury in Uninsured and Underinsured Diabetic African American Men and Putative Role of Meprin Metalloproteases in Diabetic Nephropathy. Int J Nephrol 2018:6753489
Bylander, John E; Ahmed, Faihaa; Conley, Sabena M et al. (2017) Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes. J Diabetes Res 2017:9035038
Kumar, Nitin; Nakagawa, Pablo; Janic, Branislava et al. (2016) The anti-inflammatory peptide Ac-SDKP is released from thymosin-?4 by renal meprin-? and prolyl oligopeptidase. Am J Physiol Renal Physiol 310:F1026-34
Martin, Barry Lee; Conley, Sabena Michelle; Harris, Regine Simone et al. (2016) Hypoxia Associated Proteolytic Processing of OS-9 by the Metalloproteinase Meprin ?. Int J Nephrol 2016:2851803
Niyitegeka, Jean-Marie V; Bastidas, Adam C; Newman, Robert H et al. (2015) Isoform-specific interactions between meprin metalloproteases and the catalytic subunit of protein kinase A: significance in acute and chronic kidney injury. Am J Physiol Renal Physiol 308:F56-68