The role of Tamm-Horsfall protein in acute kidney injury and transition to chronic kidney disease

Abstract

Acute kidney injury (AKI) is a major determinant of mortality and morbidity in hospitalized patients. Understanding the pathophysiology of AKI is essential for the development of therapy. Furthermore, AKI itself can lead to de novo chronic kidney disease (CKD) and progression towards end stage kidney disease. This application proposes to study the role of Tamm-Horsfall protein (THP) in regulating the susceptibility and severity of AKI and the transition to CKD. THP is expressed exclusively in the kidney by cells of the thick ascending limbs (TAL) of Henle. THP deficiency enhances the severity of AKI, and this protein has a protective role by inhibiting inflammatory signaling in proximal tubules and regulating macrophage function. The immediate goal of the current proposal is to advance our developing knowledge of the role of THP in immunomodulating kidney injury and repair and use this knowledge to transition into therapeutic applications. The central hypothesis for this application is that THP is essential to promoting recovery from AKI and progression to CKD by promoting tubular repair and enhancing the activity of renal macrophages needed for healing. This hypothesis will be investigated using 2 specific aims. Aim 1 will define the role of THP on tubular injury/repair and homeostasis of renal macrophages during AKI. Aim 2 will define the role of THP long term fibrosis and progression to CKD. This research is innovative, because it will uncover novel regulatory functions for THP in injury and repair and will pave the way to develop novel therapeutic strategies using recombinant THP. (AU)