The overall goal of the current proposal is to understand the mechanisms by which targeting the sphingolipid pathway can prevent or attenuate progressive kidney fibrosis. ~20-40M people in the United States have kidney diseases and new treatments are urgently needed. Targeting the sphingolipid pathway serves as an important area for biological research that will undergird novel therapeutic interventions for the treatment of progressive kidney fibrosis. Sphingosine 1-phosphate (S1P) is the naturally occurring ligand of the S1P receptors (S1PR) and is present in both extracellular and intracellular compartments. The effects of extracellular S1P are mediated through S1PR1-5, which are differentially expressed by a variety of cell types. Intracellular S1P is controlled by manipulating S1P synthesis, degradation, or export. Intracellular S1P is a key signaling molecule that has multifunctional roles, depending on its compartmentalization. Intracellular S1P is generated by phosphorylation of sphingosine by two sphingosine kinases (Sphk1 and Sphk2). Sphk1 is localized to the cytoplasm and Sphk2 localized to the nucleus, mitochondria, and endoplasmic reticulum. We observed markedly attenuated renal fibrosis in Sphk2-/- mice compared to Sphk1-/- or WT mice and in mice with tissue specific deletion of Sphk2 in pericyte/perivascular cells. S1P generated by Sphk2 binds to and inhibits histone deacetylase (HDAC) activity and enhances gene expression. Recently Spns2 has been identified as an S1P export pathway; inhibition of S1P transport increases cytoplasmic S1P and inhibits production of fibrogenic factors in cultured kidney cells, and Spns2 deficient mice are associated with inflammatory disease conditions. Spns2 is highly expressed in proximal tubule, endothelium and pericytes. Lastly we found that a lead Spns2 inhibitor attenuated AKI. These findings lead us to hypothesize that compartmental control of S1P is a critical determinant of progressive kidney fibrosis.
Aim 1 will test the hypothesis that nuclear Sphk2-deficiency protects mice from kidney fibrosis. We will determine whether the enzymatic activity or the nuclear localization of Sphk2 are necessary for fibrosis.
Aim 2 will test the hypothesis that Spns2 inhibition or Spns2 deficiency protects mice from progressive kidney fibrosis. We will determine whether 1) global Spns2 deficient mice are protected from fibrosis and 2) mice treated with a lead Spns2 inhibitor, are protected from fibrosis.
Aim 3. Will test the hypothesis that control of kidney parenchymal export of S1P is critical in attenuating fibrosis. We hypothesize that the protective effect is due to decreased export of S1P in proximal tubule cells, endothelial cells or pericytes. We will generate pericyte, endothelial and proximal tubule Spns2-/- mice and determine the effect on fibrosis. We will perform in vitro studies and determine the role of compartmental control of S1P pericytes, endothelial cells or proximal tubule cells factors that control pericyte to myofibroblast transition. We believe that these studies will lead to further understanding of the pathogenesis of progressive kidney fibrosis and provide the foundation for the development of novel therapeutics agents.
Kidney disease, and in particular acute kidney injury (AKI) and chronic kidney disease (CKD) are major economic and public health concerns in the United States and world-wide with ever increasing rates of hospitalization. They are interrelated and it is well known that AKI can transition to CKD and end stage renal disease and ultimately shortened lifespan. The development of effective treatments for progressive fibrosis following AKI is urgently needed and depends on a precise understanding of the molecular, cellular and immunological basis for AKI-CKD transition. The major goal of the current proposal is to further investigate how modulation of the sphingolipid pathway protects kidneys from AKI and its progression to fibrosis and to examine new mechanisms, including manipulation of intracellular levels of sphingosine 1- phosphate (an important lipid signaling molecule), that can be targeted to promote this protective effect.
| 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 |
| 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 |
| 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 |
| 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 |
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