Roles of heat-shock protein 90 and its four domains (N, LR, M and C) in calcium oxalate stone-forming processes

Abstract

Human heat-shock protein 90 (HSP90) has four functional domains, including NH 2 -terminal (N), charged linker region (LR), middle (M) and COOH-terminal (C) domains. In kidney stone disease (or nephrolithiasis/urolithiasis), HSP90 serves as a receptor for calcium oxalate monohydrate (COM), which is the most common crystal to form kidney stones. Nevertheless, roles of HSP90 and its four domains in kidney stone formation remained unclear and under-investigated. We thus examined and compared their effects on COM crystals during physical (crystallization, growth and aggregation) and biological (crystal–cell adhesion and crystal invasion through extracellular matrix (ECM)) pathogenic processes of kidney stone formation. The analyses revealed that full-length (FL) HSP90 obviously increased COM crystal size and abundance during crystallization and markedly promoted crystal growth, aggregation, adhesion onto renal cells and ECM invasion. Comparing among four individual domains, N and C domains exhibited the strongest promoting effects, whereas LR domain had the weakest promoting effects on COM crystals. In summary, our findings indicate that FL-HSP90 and its four domains (N, LR, M and C) promote COM crystallization, crystal growth, aggregation, adhesion onto renal cells and invasion through the ECM, all of which are the important physical and biological pathogenic processes of kidney stone formation. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04483-z.

Resveratrol inhibits calcium oxalate crystal growth, reduces adhesion to renal cells and induces crystal internalization into the cells, but promotes crystal aggregation

“…In this study, we used an in vitro method with a reliable aggregation index previously established ( Chaiyarit and Thongboonkerd, 2017 ) to investigate CaOx crystal aggregation. Our finding is consistent with previous studies reporting the promoting effects of diosmin ( Khamchun et al, 2021 ), quercetin ( Chaiyarit et al, 2024 ), heat shock protein 90 ( Yoodee et al, 2022 ), and desialylated uromodulin ( Viswanathan et al, 2011 ). The promoting activity of these molecules on CaOx crystal aggregation has been thought to occur via the bridge-like activity of the molecules that can bind to the surfaces of adjacent CaOx crystals, thereby forming the crystal clusters, clumps or aggregates ( Fig.…”