Acute kidney injury (AKI) is a common disorder with an exceedingly high morbidity and mortality. Inflammation plays an important role in the pathogenesis of AKI. Molecules are exists to control inflammatory process however, the mechanisms through these molecules suppress inflammation and how inflammatory processes overcome the suppression to induce renal injury are remains poorly understood. The objective of this application is to determine the mechanisms by which activation of signaling pathways by netrin-1 lead to protection of kidney against ischemic reperfusion injury. Netrins are a family of neuronal guidance cues highly expressed in vascular endothelial cells and their receptors were expressed both in circulating leukocytes and endothelial cells. Our central hypothesis is that netrin-1 inhibits leukocyte migration and inflammation acting via the UNC5B receptor expressed on the leukocytes and vascular endothelial cells resulting in reduced inflammation and increased perfusion of the kidney. This hypothesis is based on our extensive preliminary data which clearly indicate that netrin-1 expression down regulated in endothelial cells after ischemia reperfusion of kidney and administration of recombinant netrin-1 protected ischemia reperfusion injury of the kidney and reduced inflammation. We plan to test our hypothesis and achieve the objective of this application by pursuing the following three specific aims: #1) Determine the receptor(s) which mediate netrin-1 protective effect against ischemia reperfusion of the kidney. #2) Determine the signaling mechanism through which netrin-1 mediates effect on renal parenchymal cells and leukocytes. #3) Determine the mechanism of netrin-1 mediated protection against ischemic renal injury. The proposed work is innovative because the role of netrin-1 and their receptors in AKI is unknown. Our expectation is that the results will provide novel insights into the mechanisms whereby netrin-1 signaling regulate inflammation and subsequent protection of structural and functional damage. It will also discover new information defining the regulation of epithelial and endothelial functions by netrin-1 signaling in response to ischemic renal injury.

Public Health Relevance

The proposed studies will elucidate the key role of netrin-1 receptors in the netrin-1 mediated protection of kidney against ischemia reperfusion injury. They will also define the central role of kidney netrin-1 receptor signaling in regulating migration of inflammatory cells infiltrate into kidney. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of recombinant netrin-1 and other signaling pathway inhibitors for the prevention or treatment of acute renal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083379-04
Application #
8311014
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$282,150
Indirect Cost
$94,050
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Ranganathan, Punithavathi; Jayakumar, Calpurnia; Mohamed, Riyaz et al. (2014) Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury. Am J Physiol Renal Physiol 307:F183-94
Ranganathan, Punithavathi; Mohamed, Riyaz; Jayakumar, Calpurnia et al. (2014) Guidance cue netrin-1 and the regulation of inflammation in acute and chronic kidney disease. Mediators Inflamm 2014:525891
Doi, Kent; Noiri, Eisei; Nangaku, Masaomi et al. (2014) Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit. Nephrol Dial Transplant 29:73-80
Lewandowska, Lidia; Matuszkiewicz-Rowi?ska, Joanna; Jayakumar, Calpurnia et al. (2014) Netrin-1 and semaphorin 3A predict the development of acute kidney injury in liver transplant patients. PLoS One 9:e107898
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Mohamed, Riyaz; Ranganathan, Punithavathi; Jayakumar, Calpurnia et al. (2014) Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice. J Mol Med (Berl) 92:1245-56
Ranganathan, Punithavathi; Jayakumar, Calpurnia; Navankasattusas, Sutip et al. (2014) UNC5B receptor deletion exacerbates tissue injury in response to AKI. J Am Soc Nephrol 25:239-49
Mohamed, Riyaz; Jayakumar, Calpurnia; Ramesh, Ganesan (2013) Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6. Lab Invest 93:933-45

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