Transcription Factor β-Catenin Plays a Key Role in Fluid Flow Shear Stress-Mediated Glomerular Injury in Solitary Kidney.

Ellen T. McCarthy,Mukut Sharma,Trupti Joshi,Jianping Zhou,Uri S. Alon,Daniel P. Heruth,Mark L. Johnson,Varun C. Boinpelly,Tarak Srivastava,R. Scott Duncan,Lakshmi Priya,Yuexu Jiang,Jan Novak,Ram Sharma,Virginia J. Savin,Robert E. Garola,Mohammad H. Rezaiekhaligh,Mohammed Farhan Ali

doi:10.3390/cells10051253

Abstract

Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo. FFSS-treated cultured podocytes show upregulated AKT-GSK3β-β-catenin signaling. The present study was undertaken to confirm (i) the activation of β-catenin signaling in podocytes in vivo using unilaterally nephrectomized (UNX) TOPGAL mice with the β-galactosidase reporter gene for β-catenin activation, (ii) β-catenin translocation in FFSS-treated mouse podocytes, and (iii) β-catenin signaling using publicly available data from UNX mice. The UNX of TOPGAL mice resulted in glomerular hypertrophy and increased the mesangial matrix consistent with hemodynamic adaptation. Uninephrectomized TOPGAL mice showed an increased β-galactosidase expression at 4 weeks but not at 12 weeks, as assessed using immunofluorescence microscopy (p < 0.001 at 4 weeks; p = 0.16 at 12 weeks) and X-gal staining (p = 0.008 at 4 weeks; p = 0.65 at 12 weeks). Immunofluorescence microscopy showed a significant increase in phospho-β-catenin (Ser552, p = 0.005) at 4 weeks but not at 12 weeks (p = 0.935) following UNX, and the levels of phospho-β-catenin (Ser675) did not change. In vitro FFSS caused a sustained increase in the nuclear translocation of phospho-β-catenin (Ser552) but not phospho-β-catenin (Ser675) in podocytes. The bioinformatic analysis of the GEO dataset, #GSE53996, also identified β-catenin as a key upstream regulator. We conclude that transcription factor β-catenin mediates FFSS-induced podocyte (glomerular) injury in solitary kidney.

Highlights

Persistent hyperfiltration is one of the major causes of a loss of glomerular function and the progression of chronic kidney disease (CKD), but the underlying mechanism is not well understood
We demonstrated that fluid flow shear stress (FFSS) induces the activation of the “PGE2 -COX2EP2” axis and the “AKT-GSK3β-β-catenin” pathway in podocytes in vitro
In contrast to the mesangial matrix expansion, no significant increase in the mesangial cell count was observed in the glomeruli, except in the outer cortical glomeruli at 12 weeks. These results show that unilateral nephrectomy in TOPGAL mice resulted in increased glomerular hypertrophy and increased the mesangial matrix, especially in the juxtamedullary glomeruli early and in the outer cortical glomeruli later, as part of the glomerular hemodynamic adaptation following UNX

Summary

Introduction

Persistent hyperfiltration is one of the major causes of a loss of glomerular function and the progression of chronic kidney disease (CKD), but the underlying mechanism is not well understood. Our laboratory and a few other groups have recently started investigating biomechanical forces that mediate the effects of hyperfiltration in the glomerulus [3,4,5,6]. Two types of biomechanical forces are believed to mediate the effects of hyperfiltration on glomerular function and structure, namely, tensile stress and fluid flow shear stress (FFSS), which were recently reviewed by Srivastava et al [5,6]. The increased intra-capillary pressure, working outwardly perpendicular to the direction of blood flow in the capillary, stretches foot processes and generates tensile stress on the basolateral aspect of podocytes [5]. The second biomechanical force, FFSS, is generated on podocyte soma and primary processes by the glomerular ultrafiltrate flowing through Bowman’s space [5,7]. We have shown a 1.5–2.0-fold increase in the calculated FFSS over podocytes in solitary kidney in mice and rats [9]

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