Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the nature of the relationship is not clear. We demonstrated that renal capillary density is permanently compromised in rats following AKI induced by ischemia reperfusion (I/R). AKI alters renal hemodynamic responses and predisposes to salt- sensitive hypertension and we demonstrated that preservation of vascular structure following I/R attenuates high-salt induced CKD. However, immunosuppression also blocked salt-induced hypertension and CKD following AKI. Moreover, preliminary studies on the contralateral kidney following unilateral AKI (termed "remote/indirect" AKI) demonstrates that circulating factors alter hemodynamic function in the absence of direct injury. Our overarching hypothesis is that AKI alters chronic renal function due to vascular dropout and activation and differentiation of T lymphocytes, which have independent and synergistic effects to promote hypertension and CKD. Rats will be studied in models of "direct AKI" injury and "remote AKI" in combination with reduced renal mass and high salt diet.
Specific aim 1 will test the hypothesis that AKI promotes the persistent deposition of T cells and their cytokine profiles are modulated by the type of injury (direct vs. remote), reduced renal mass, and dietary salt. These studies will utilize FACS analysis and characterize T helper differentiation by assessing cytokine profiles produced by T-cells, and the activation of antigen presenting cells following injury.
Specific aim 2 will test the hypothesis that AKI primed lymphocytes influence renal hemodynamic function, hypertension and CKD following direct or remote renal injury. These studies will utilize both immunosuppressive and adoptive transfer approaches to evaluate alterations in hemodynamic control. Additional studies using adoptive transfer into injured or non-injured T cell deficient ras will be used to evaluate the distinct and synergistic interactions of AKI and injury activated T cells on salt induced CKD. Finally, Specific aim 3 will evaluate the hypothesis that T cell differentiation induced by high salt diet (following direct injury), is a key step in the AKI to CK transition. These studies will use strategies to block specific co-stimulatory and chemokine pathways which may specifically enhanced T cell differentiation and determine if commonly utilized anti-hypertensive treatments influence T-cell differentiation in response to high salt die following AKI.

Public Health Relevance

Acute kidney injury (AKI) is the most common renal disease requiring hospitalization is becoming a widely recognized contributor toward the development of chronic kidney disease. Progressive kidney disease following AKI may result from incomplete tissue repair responses, such as a reduction in the number of renal micro-vessels or the activation of immune responses. The current program will allow the evaluation the potential interaction between altered immune function on altered vascular function as it may be related to the transition of acute kidney injury to chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063114-11
Application #
8636448
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2003-07-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
11
Fiscal Year
2014
Total Cost
$305,370
Indirect Cost
$109,620
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Basile, David P; Leonard, Ellen C; Beal, Alisa G et al. (2012) Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity. Am J Physiol Renal Physiol 302:F1494-502

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