Promoting activities of human cyclophilin A on calcium oxalate stone formation at crystal growth, aggregation and crystal-cell adhesion phases

Abstract

Kidney stone is a specialized form of biomineralization involving complex interactions between crystals and urinary macromolecules. Renal tubular cells secrete cyclophilin A (CyPA), a protein whose elevated level is associated with various kidney diseases. Nevertheless, its role in kidney stone formation has not previously been explored. This study thus aimed to investigate roles of CyPA in kidney stone formation through various calcium oxalate (CaOx) crystal assays. Recombinant human CyPA was generated to mimic its secretory form excreted into the urine. Crystal assays yielded the first evidence demonstrating that CyPA significantly promoted CaOx growth, aggregation and crystal-cell adhesion, all of which are the critical steps during initial CaOx stone formation. Despite the lack of specific Ca2+-binding and Ox2−-binding domains and its inability to bind free Ca2+/Ox2− ions in solution, CyPA demonstrated a distinct ability to bind CaOx crystals. Upon binding, CyPA facilitated further CaOx growth, aggregation of adjacent crystals and crystal-cell adhesion. These findings unravel a novel mechanism of kidney stone pathogenesis, expanding the known functions of CyPA. This research also provides solid evidence of how CyPA became one of the compositions in the stone matrix and highlights its potential to be a therapeutic/preventive target for management/prevention of kidney stone disease.