Role of Renal Tubular Wnt/Beta-catenin in Proteinuric Kidney

Abstract

Accumulating evidences have demonstrated multiple and discrepancy roles of Wnt/β-catenin signaling in progressive chronic kidney disease (CKD). In this study, we present the biphasic and dual roles of renal tubular β-catenin during proteinuric nephropathy. A dynamic trend in Wnt/β-catenin signaling pathway was found in HK-2 cells with upregulated and downregulated activity in acute and prolonged exposure to high dose albumin, respectively. Silencing of β-catenin further augmented the proapoptotic phenotype induced by albumin overload cells. A similar observation was detected in a mouse model with overload albuminuria. The renal cortical β-catenin expression was enhanced at the early phase but abrogated at the late phase. During the late phase, heightened tubular cell death was accompanied by a further aggravated albuminuria. To address the role of enhanced tubular β-catenin, we generated a novel transgenic mouse line (Tubcat) which conditionally expresses stabilized β-catenin in renal tubules. Albumin-overloaded Tubcat mice displayed more severe albuminuria and higher BUN levels compared to wild type control. These adverse renal outcomes coincided with the onset of intrarenal inflammation, as evidenced by upregulated chemokine synthesis and tubulointerstitial macrophage infiltration. Taken together, these findings suggest that activated tubular β-catenin promotes renal inflammation during the early phase of proteinuric CKD, thereafter the downregulation of β-catenin in the late phase mediates tubular apoptosis. In summary, the imbalance of Wnt/β-catenin signaling is detrimental throughout the progression of CKD and restoring the balance of this pathway could provide a scientific basis for therapeutic intervention.