Acute kidney injury (AKI) is a common problem in hospitalized patients, which increases length of stay, morbidity and mortality. Unfortunately, patients who appear to recover from AKI are at significantly increased risk of chronic and end-stage renal disease over time. Currently there are no FDA approved drugs or biologic agents to treat AKI. A better understanding of the pathophysiology of AKI and the mechanisms of resistance to AKI should reveal novel therapeutic options for this disease. Major causes of AKI include: ischemia-reperfusion (IR) injury and nephrotoxic drugs (such as cisplatin, a chemotherapeutic agent), which induce direct toxicity to kidney cells and provoke the immune system. Animal models of AKI have revealed that numerous pro- inflammatory leukocytes promote renal tissue damage and loss of function. On the contrary, regulatory T cells (Tregs), which are anti-inflammatory lymphocytes, respond to and protect the kidney from injury and promote recovery from AKI. During work on the current K01 award by the applicant, it was discovered that expression of the co-inhibitory receptor programmed death 1 (PD-1) on the cell surface of Tregs and the ability to generate IL-10 are absolutely required for their protective action in kidney IR. Several lines of experimental evidence from other laboratories suggest that PD-1 engagement on Tregs promotes IL-10 production by Tregs, but this possibility has never been directly tested. In support of a protective role for PD-1 and PD-L1 in AKI, treatment of naive mice with a blocking antibody to PD-L1 renders mice highly susceptible to sub-threshold ischemia that does not cause tissue injury or loss of function in control antibody treated mice. Based on these findings we hypothesize that PD-1/PD-L1 interactions promote Treg IL-10 production and constitute a vital component of the natural defense against AKI.
Specific Aim 1 will determine the role of PD-1 in IR- and cisplatin-induced AKI in mouse models using both PD-1 knockout mice (compared to wild-type littermates) and PD-1 or PD-L1 blocking antibodies in wild-type mice.
Specific Aim 2 will test the hypothesis that PD-1 engagement on Tregs enhances their activity in an IL-10 dependent manner. This will be examined first in vitro by exposing isolated Tregs to plate-bound PD-L1 Fc chimeric molecules (or a control Fc chimera) and measuring the response of Tregs to PD-1 engagement at the mRNA and protein level. Second, the ability of PD-1 engagement in vitro, to enhance subsequent Treg activity in vivo will be tested in the established kidney IR model. Finally, the role of IL-10 in PD-1-stimulated Treg activity will be determined by comparing the in vivo protective ability of wild-type and IL-10 knockout Tregs in the kidney IR model. The results of these specific aims will yield important information about the role of PD-1 and PD-L1 in the natural protective response in AKI. Furthermore, the functional significance of PD-1 engagement on Tregs will be investigated. These are previously unexplored questions that may reveal novel targets to prevent or ameliorate AKI. The knowledge gained through this project will form the basis of independent publications and an individual R01 application by the PI.
Acute kidney injury is a major problem for hospitalized patients, which is costly in terms of length of hospital stay, mortality and financial burden on th healthcare system. Treatment strategies are limited to supportive care and new therapeutic interventions are urgently needed. Exploring intrinsic kidney-protective pathways, such as the interactions between PD-1 and PD-L1 will reveal new therapeutic targets to prevent, or speed recovery from acute kidney injury.
|Kinsey, Gilbert R (2015) Myeloid Cell HO-ming in AKI. J Am Soc Nephrol 26:2067-9|
|Jaworska, Katarzyna; Ratajczak, Joanna; Huang, Liping et al. (2015) Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J Immunol 194:325-33|
|Bajwa, Amandeep; Rosin, Diane L; Chroscicki, Piotr et al. (2015) Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury. J Am Soc Nephrol 26:908-25|
|Kinsey, Gilbert R (2014) Macrophage dynamics in AKI to CKD progression. J Am Soc Nephrol 25:209-11|