Acute kidney injury is a common and serious complication of medical and surgical diseases that has significant attributable morbidity and mortality. Multiple epidemiological studies suggest a relationship of acute kidney injury with the subsequent development of chronic kidney disease. The overall goal of this project is to elucidate the biologic basis for the cytoprotective effects of heme oxygenase-1 (HO-1) and generate relevant and feasible therapeutic strategies based on induction of HO-1 expression in acute kidney injury. During the previous project period we focused on the mechanisms underlying the protective effects of HO-1 and the molecular regulation of HO-1 gene expression in acute kidney injury. Our studies have (i) identified a novel enhancer sequence that regulates human HO-1 gene expression, (ii) generated a number of conditional cell/tissue specific HO-1 mouse strains, (iii) the discovery that HO-1 can regulate autophagy in acute kidney injury, and (iv) HO-1 regulates the trafficking of myeloid derived immune cells, and lack of myeloid HO-1 impairs recovery from acute kidney injury and results in increased fibrosis. Using the knowledgebase generated during the last funding cycle, we will address the central hypothesis that HO-1 expression regulates cross-talk between the renal proximal tubules and myeloid cells, and HO-1 upregulation either in tubules or myeloid cells will not only protect against acute kidney injury, but also the subsequent evolution of chronic kidney disease. We will execute the following specific aims:
Aim 1 : To test the hypothesis that proximal tubule HO-1 expression affects differentiation, infiltration, and trafficking of myeloid cells in acute kidney injury;
Aim2 : To test the hypothesis that myeloid cell HO-1 expression modulates inflammation in acute kidney injury and the transition to chronic kidney disease;
and Aim 3 : To test the hypothesis that HO-1 induction using small molecules will provide protection against acute kidney injury and the transition to chronic kidney disease. Successful completion of the studies in this renewal application will (i) provide key information on the protective mechanisms in acute kidney injury, (ii) highlight the role for HO-1 in orchestrating the cross-talk between the renal tubules and myeloid cells, and (iii) provide novel candidate agents to be potentially utilized in the preventio and treatment of acute kidney injury, thereby paving the way for a new therapeutic approach in this disease.
Acute kidney injury is a condition that is associated with significant morbidity and mortality particularly in critically ill patients. The goal of this projet is to understand the protective mechanisms in the pathogenesis of acute kidney injury focusing on an anti-oxidant and anti- inflammatory protein, heme oxygenase-1. The results of the proposed studies will also be applicable to other diseases associated with inflammation and oxidative stress such as sepsis, acute lung injury, and heart disease wherein heme oxygenase-1 is known to exert a protective effect.
| Lever, Jeremie M; Yang, Zhengqin; Boddu, Ravindra et al. (2018) Parabiosis reveals leukocyte dynamics in the kidney. Lab Invest 98:391-402 |
| Bolisetty, Subhashini; Zarjou, Abolfazl; Agarwal, Anupam (2017) Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury. Am J Kidney Dis 69:531-545 |
| George, James F; Lever, Jeremie M; Agarwal, Anupam (2017) Mononuclear phagocyte subpopulations in the mouse kidney. Am J Physiol Renal Physiol 312:F640-F646 |
| Surolia, Ranu; Karki, Suman; Wang, Zheng et al. (2016) Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections. Am J Physiol Lung Cell Mol Physiol 311:L928-L940 |
| Ayer, Anita; Zarjou, Abolfazl; Agarwal, Anupam et al. (2016) Heme Oxygenases in Cardiovascular Health and Disease. Physiol Rev 96:1449-508 |
| Srivastava, Ritesh K; Li, Changzhao; Weng, Zhiping et al. (2016) Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype. Sci Rep 6:34865 |
| Walker, Vyvyca J; Agarwal, Anupam (2016) Targeting Iron Homeostasis in Acute Kidney Injury. Semin Nephrol 36:62-70 |
| Li, Changzhao; Srivastava, Ritesh K; Weng, Zhiping et al. (2016) Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation: Chemical Chaperones as Potential Novel Antidotes. Am J Pathol 186:2637-49 |
| Páll, Alida; Czifra, Árpád; Sebestyén, Veronika et al. (2016) Hemodiafiltration and hemodialysis differently affect P wave duration and dispersion on the surface electrocardiogram. Int Urol Nephrol 48:271-7 |
| Bolisetty, Subhashini; Traylor, Amie; Joseph, Reny et al. (2016) Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol 310:F385-94 |
Showing the most recent 10 out of 58 publications
