lmmunomodulatory roles of renal lymphatic endothelial cells in Acute Kidney Injury

Texas A&M University Health Science Ctr, College Station TX

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Abstract

PROJECT SUMMARY In the United States an estimated 50% of ICU patients develop AKI and is associated with a 50% mortality rte. A single occurrence of AKI predisposes a patient to develop chronic conditions such as Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD), conditions which decrease quality of life and may be fatal. Increasingly, research demonstrates that AKI induced injury promotes persistent renal inflammation and fibrosis driving progression to CKD and ESRD. Understanding mechanisms by which renal inflammation may be regulated would therefore allow development of targeted renal therapeutic environments. Inflammation associated lymphangiogenesis is responsible for maintaining tissue homeostasis through uptake of fluids, macromolecules, proteins, and immune cell trafficking. Upon AKI insult lymphatic growth factors Vascular endothelial growth factor D (VEGF-D) and VEGF-C are increased within the kidney. Lymphatic research has identified immunomodulatory roles of LECs such as expression of MHCs, chemokine receptors, and antigen presentation. The lab has demonstrated increased renal lymphangiogenesis in models of AKI alters adaptive immune cell presence and reduces renal fibrosis. However, how LECs regulate AKI associated inflammation and recovery is still unknown. The long-term goal of this study is to identify how immunomodulatory roles of LECs impact the renal immune response and recovery in AKI. The proposal’s overall objective is to identify how the adaptive immune response is altered in AKI with increased renal lymphatic density and how these immune cell populations are altered upon deletion of a known LEC immunomodulatory molecule. The central hypothesis is that renal LECs regulate inflammation through direct lymphatic-immune cell interactions and regulate immune cell clearance from the tissue, altering pathophysiological outcomes in AKI. Directed by strongly supportive preliminary data the hypothesis will be tested by two specific aims: Aim 1 Identify how increased renal lymphangiogenesis alters the adaptive immune response in AKI. Aim 2 Demonstrate LEC specific deletion of sphingosine-1-phosphate (S1P) secretion alters the T cell response and inflammation resolution in AKI. In the first aim cisplatin and ischemia-reperfusion (IR) models of AKI will assess if increased renal lymphatic density prior to injury in a mouse model of kidney specific inducible overexpression of VEGF-D (KidVD) alters adaptive immune cell populations and inflammatory progression. Preliminary data suggests increased renal lymphatic density primes the adaptive immune response and attenuates renal fibrosis. For the second aim, determining how a LEC specific deletion of S1P, a bioactive, alters renal immune cell clearance and the adaptive immune response in AKI may provide a novel renal targeted therapeutic option. To address how LECs regulate AKI associated inflammation and recovery a combination of lymphatic specific genetic models, renal injury models, and immune cell phenotyping will identify alterations in the renal immune cell response to AKI.