The ultimate goal is to develop novel therapeutic agents for treating ischemic acute kidney injury (AKI) by recruiting regulatory T cells (Treg). A growing body of evidence supports that T cells play an important role in ischemic AKI;however, the transient and early presence of T cells in the mouse ischemic kidney has only been recently reported by the investigator's team. While the depletion of T cells is associated with renoprotection, treatment with DMS to increase T cell infiltration, offers renoprotection too. This paradox appears to be associated with the novel findings that DMS preferentially recruits Treg into the kidney. The therapeutic value of Treg has been recognized, but hampered by the problems arising from isolating and expanding desirable Treg. Our central hypothesis is that DMS recruits Treg to suppress inflammatory reactions in AKI. To facilitate Treg trafficking study and Treg isolation and quantification, we will use bicistronic transgenic mice in which all Treg carry enhanced green fluorescent protein (EGFP). There are 3 specific aims:
Aim 1) To characterize CD4+ T cells recruited by DMS in healthy mouse kidneys and to determine the mechanisms underlying Treg recruitment by DMS. Three independent and complimentary approaches will be used to explore T cell recruitment by DMS: i) Immunofluorescent staining of renal sections with antibodies specific to Treg or T effectors;ii) an """"""""immunolabeling pulse-chase"""""""" study by in-vivo labeling of intravascular CD4+ T cells and tracking their migration in the kidney;and iii) intravital microscopy to directly visualize EGFP+ cells or labeled CD4+ T cells migration in the kidney. We will determine whether DMS induces de novo conversion of Treg from naove T cells or homing of Treg and expand our chemokine search using microarray and proteomics approaches. To explore mechanisms of DMS stimulation of chemokines, we will use cultured renal tubular cells which are major chemokine producers in kidney, to identify downstream signal transduction pathways.
In Aim 2, the CD4+ T cells recruited by DMS during AKI will be characterized to delineate the role of Treg in DMS induced renoprotection. The function of Treg will be investigated by measuring proteins and mRNA involved in Treg suppression functions and by examining cell-cell interactions between Treg and other inflammatory cells. Treg-dependency will be studied by depleting mouse Treg with anti-CD25 antibodies or impairing Treg with anti-CLTA4 antibodies.
In Aim 3, the mechanisms of DMS effects on Treg recruitment and renoprotection will be studied using expression microarrays and phosphoproteomics approaches to search for signaling transduction pathways involved in DMS effects. Narrowing down the exact action of DMS will not only enhance our understanding on Treg function and migration, but also provide a platform for the screening of new renoprotective drugs with specific pharmacological action. Our studies will provide the foundation for developing the Treg-recruiting agents such as DMS into a first-in-class drug for ischemic AKI and possibly many other diseases such as diabetes and arthritis that are mediated by activated T cells.
A novel drug has been identified which prevents kidney injuries caused by lack of blood circulation. This drug recruits regulatory T cells to the kidney and protects the kidney by suppressing other inflammatory cells. By studying how this drug recruits regulatory T cells, we can develop new treatments not only for kidney injuries, but also for many other diseases caused by abnormalities in the immune system, such as diabetes and arthritis.
|Lee, Chien-Te; Ng, Hwee-Yeong; Lee, Yueh-Ting et al. (2016) The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics. Am J Physiol Renal Physiol 310:F230-6|
|Lee, Chien-Te; Lien, Yeong-Hau H; Lai, Li-Wen et al. (2012) Variations of dietary salt and fluid modulate calcium and magnesium transport in the renal distal tubule. Nephron Physiol 122:19-27|
|Mustafa, Esmat; Lai, Liwen; Lien, Yeong-Hau H (2012) Rapid recovery from acute kidney injury in a patient with metformin-associated lactic acidosis and hypothermia. Am J Med 125:e1-2|
|Lai, Li-Wen; Yong, Kim-Chong; Lien, Yeong-Hau H (2012) Pharmacologic recruitment of regulatory T cells as a therapy for ischemic acute kidney injury. Kidney Int 81:983-92|
|Lee, Chien-Te; Chen, Hung Chun; Ng, Hwee-Yeong et al. (2012) Renal adaptation to gentamicin-induced mineral loss. Am J Nephrol 35:279-86|
|Lien, Yeong-Hau H; Lai, Li-Wen (2011) Pathogenesis, diagnosis and management of paraneoplastic glomerulonephritis. Nat Rev Nephrol 7:85-95|
|Lee, Chien-Te; Ng, Hwee-Yeong; Lien, Yeong-Hau et al. (2011) Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 34:87-94|