Acute kidney injury (AKI) is a major healthcare concern, affecting ~13.3 million patients per year world-wide and causing ~1.7 million deaths. Despite the resolution of renal injury in many survivors, patients with AKI are predisposed to developing chronic kidney disease. Easing this burden will require new and effective therapies, but their development has been hindered by the limited knowledge of the injury mechanisms in AKI. A common cause of AKI is renal ischemia/reperfusion injury (IRI), characterized by impairment of oxygen and nutrient supply triggering renal tubular epithelial cell (TEC) injury upon reperfusion. Renal IRI is accompanied by a systemic inflammatory response, but the contribution of this response to AKI is not fully understood. Our group showed that a recognized biomarker of inflammation, C-reactive protein (CRP), exacerbates injury in a human CRP transgenic (CRPtg) mouse model of bilateral renal IRI. The worsened outcome seen in CRPtg mice involves human CRP-mediated alteration of the subtypes of myeloid derived suppressor cells (MDSCs) infiltrating the injured kidney. Indeed, targeted lowering of human CRP prior to renal IRI both normalizes MDSC subtype balance and protects the kidney. Relevant literature show that both pharmacological inhibition of glycogen synthase kinase 3 (GSK3) and specific renal proximal TEC deletion of the beta isoform (GSK3?) attenuate AKI and later renal fibrosis, suggesting a role for GSK3 kinase activity in balancing successful and maladaptive renal repair after AKI. My preliminary data shows that CRP dose-dependently modulates GSK3? phosphorylation (and thus GSK3? kinase activity) in vitro in wild type bone marrow-derived MDSCs. I therefore hypothesize that CRP binding to the inhibitory type Fc gamma receptor IIB (Fc?RIIB), which is expressed by renal cells such as MDSCs and TECs, leads to downstream modulation of GSK3? kinase activity, thereby effecting signaling cascades propelling AKI. Through studying this novel causal signaling pathway new therapeutic targets for AKI could be revealed. In addition, this project describes the dissertation research that corresponds to the pre-doctoral training planned in cooperation between the Principal Investigator (myself), Sponsor (Alexander Szalai, PhD), and Co-Sponsor (Anupam Agarwal, MD). This project will provide me an opportunity for skill development in molecular, cellular, and immunohistochemical techniques, mouse disease and surgical manipulation, analysis of the mechanisms and processes underlying a pathophysiological response and therein the human translatable applications. The successful completion of the research and training detailed within this project would therefore produce a highly proficient Immunologist specialized in Nephrology with a range of skills applicable to many research areas.
Acute kidney injury is a major healthcare concern, affecting ~13.3 million patients annually worldwide, and of those patients ~1.7 million die. This research aims to contribute to the knowledge of the kidney injury process so as to provide a novel targeted therapeutic approach that might decrease the burden of acute kidney injury.
| Jimenez, Rachel V; Wright, Tyler T; Jones, Nicholas R et al. (2018) C-Reactive Protein Impairs Dendritic Cell Development, Maturation, and Function: Implications for Peripheral Tolerance. Front Immunol 9:372 |
