The overall goal of the research proposed is to understand the mechanisms of acute kidney injury (AKI) to enable the design of new therapeutic agents to prevent and treat this devastating disorder. One strategy that has evolved over the last few years involves sphingosine 1-phosphate receptor (S1PR) agonists. These compounds abrogate the pathology associated with ischemia-reperfusion injury (IRI) of the kidney and other organs. Cellular sphingolipids are metabolized rapidly to a series of bioactive intermediates including sphingosine 1-phosphate (S1P) following stimulation of cell membrane receptors or injury to plasma membranes. S1P has diverse cellular signaling responses on immune and nonimmune cells through cell surface receptors. This proposal focuses on the extracellular effects of S1P analogs through S1P1R and S1P3Rs on immune cells as well as cellular mechanisms of kidney inflammation and injury. Our preliminary data suggest that the protective effect of S1P1R agonists is, in part, independent of S1P agonist's canonical effect - inhibition of lymphocyte trafficking resulting in lymphopenia, because S1P1R agonists protected kidneys from IRI in Rag-1 null mice that lack T, B and NKT cells. Thus S1P1Rs on proximal tubule epithelial cells, endothelial cells or myeloid cells (dendritic cells) could serve as important cellular targets in mediating tissue protection. We also found that the absence of bone marrow derived S1P3Rs confers tissue protection. These data and the observation that S1P1Rs and S1P3Rs are the most abundantly expressed S1PRs in kidney undergird the current proposal focusing on the extrinsic cell function of these two receptor subtypes in mediating tissue protection. We hypothesize that: 1) S1P1R activation and S1P3R antagonism mediate tissue protection in epithelial and endothelial cells. 2) Ideal novel compounds in mediating tissue protection have agonist activity at S1P1R and antagonist activity of S1P3R.
Three aims are proposed:
Aims 1 tests the hypothesis that S1P1R activation on epithelial and endothelial cells mediate proximal tubule tissue protection.
Aim 2 tests the hypothesis that S1P1R activation and S1P3R deficiency attenuates dendritic cell activation of the innate immune response to IRI and Aim 3 tests the hypothesis that new compounds that possess agonist activity at S1P1R and antagonist activity at S1P3Rs are ideal characteristics in mediating tissue protection. We will use wild type and genetically modified mice, chimeric mice, immune cell ablation studies using diptheria toxin in susceptible transgenic mouse strains, adoptive transfer studies, and cultured immune cells to address mechanistic questions both in vivo and in vitro. Furthermore our methods will incorporate immunological, cell biological, molecular and physiological tools in executing each aim. Our long-term plan is to better understand the role of an important class of receptors that that will enable the development of new therapeutic interventions with compounds for S1P receptors to block the deleterious consequences of acute kidney injury.
The incidence and prevalence acute kidney injury (AKI) and its contribution to end-stage renal disease are increasing;mortality is 50 - 80% in some cases. Current treatments have failed in part due the absence of a complete understanding of the underlying pathophysiology. Our studies will identify new pathways that participate in early injury associated with AKI and identify targets for therapeutic intervention using new S1PR- directed compounds.
|Tanaka, Shinji; Okusa, Mark D (2018) Optogenetics in Understanding Mechanisms of Acute Kidney Injury. Nephron 140:152-155|
|Zuk, Anna; Palevsky, Paul M; Fried, Linda et al. (2018) Overcoming Translational Barriers in Acute Kidney Injury: A Report from an NIDDK Workshop. Clin J Am Soc Nephrol 13:1113-1123|
|Perry, Heather M; Huang, Liping; Wilson, Rebecca J et al. (2018) Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI. J Am Soc Nephrol 29:194-206|
|Lobo, Peter I; Schlegel, Kailo H; Bajwa, Amandeep et al. (2017) Natural IgM and TLR Agonists Switch Murine Splenic Pan-B to ""Regulatory"" Cells That Suppress Ischemia-Induced Innate Inflammation via Regulating NKT-1 Cells. Front Immunol 8:974|
|Stremska, Marta E; Jose, Sheethal; Sabapathy, Vikram et al. (2017) IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury. J Am Soc Nephrol 28:2681-2693|
|Abe, Chikara; Inoue, Tsuyoshi; Inglis, Mabel A et al. (2017) C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat Neurosci 20:700-707|
|Tanaka, Shinji; Inoue, Tsuyoshi; Hossack, John A et al. (2017) Nonpharmacological, Biomechanical Approaches to Control Inflammation in Acute Kidney Injury. Nephron 137:277-281|
|Bajwa, Amandeep; Huang, Liping; Kurmaeva, Elvira et al. (2017) Sphingosine Kinase 2 Deficiency Attenuates Kidney FibrosisviaIFN-?. J Am Soc Nephrol 28:1145-1161|
|Inoue, Tsuyoshi; Tanaka, Shinji; Okusa, Mark D (2017) Neuroimmune Interactions in Inflammation and Acute Kidney Injury. Front Immunol 8:945|
|Okusa, Mark D; Rosner, Mitchell H; Kellum, John A et al. (2016) Therapeutic Targets of Human AKI: Harmonizing Human and Animal AKI. J Am Soc Nephrol 27:44-8|
Showing the most recent 10 out of 44 publications