Advances in mechanical force-induced adaptive responses and pathological transition of renal tubular epithelial cells.

Abstract

Renal tubular epithelial cells (RTECs) reside in a mechanical microenvironment shaped by fluid shear stress, hydrostatic pressure, and cyclic stretch. Under physiological conditions, moderate mechanical stimulation helps maintain normal renal function by regulating cell volume, ion transport, and transcriptional programs. Tubular injury occurs when the intensity or duration of stimulation exceeds physiological tolerance. The balance between protective repair and pathological injury is determined jointly by stimulus intensity, exposure duration, and cellular adaptive capacity. Existing reviews of mechanical stress-induced kidney injury have largely emphasized pathological endpoints. The distinctive contribution of this review is to place the adaptive-to-pathological transition (the threshold at which protective mechanisms fail) and the segmental heterogeneity of tubular mechanoresponses at the center of its framework. We synthesize the molecular mechanisms by which RTECs sense and transduce mechanical signals, with particular emphasis on early adaptive responses including cytoskeletal reorganization, protein quality control, and remodeling of ion homeostasis, and we describe how persistent mechanical stimulation drives the transition from physiological adaptation to pathological injury. We further discuss quantitative and contextual thresholds for this transition, clinically relevant mechanical scenarios beyond classical obstruction, and the phase dependence of mechanosensitive therapeutic targets such as YAP/TAZ. Current research models and technologies are reviewed together with unresolved questions and future directions. By framing mechanically driven kidney disease as a continuum between adaptation and injury, this synthesis provides a theoretical basis for mechanistic studies and for timing-aware, segment-specific clinical translation in mechanical force-related kidney diseases.