Intratubular hydrodynamic forces influence tubulointerstitial fibrosis in the kidney.

PURPOSE OF REVIEW: Renal epithelial cells respond to mechanical stimuli with immediate transduction events (e.g. activation of ion channels), intermediate biological responses (e.g. changes in gene expression), and long-term cellular adaptation (e.g. protein expression). Progressive renal disease is characterized by disturbed glomerular hydrodynamics that contributes to glomerulosclerosis, but how intratubular biomechanical forces contribute to tubulointerstital inflammation and fibrosis is poorly understood. RECENT
FINDINGS: In-vivo and in-vitro models of obstructive uropathy demonstrate that tubular stretch induces robust expression of transforming growth factor beta-1, activation of tubular apoptosis, and induction of nuclear factor-kappaB signaling, which contribute to the inflammatory and fibrotic milieu. Nonobstructive structural kidney diseases associated with nephron loss follow a course characterized by compensatory increases of single nephron glomerular filtration rate and tubular flow rate. Resulting increases in tubular fluid shear stress reduce tissue-plasminogen activator and urokinase enzymatic activity, which diminishes breakdown of extracellular matrix. In models of high dietary Na intake, which increases tubular flow, urinary transforming growth factor beta-1 concentrations and renal mitogen-activated protein kinase activity are increased.
SUMMARY: In conclusion, intratubular biomechanical forces, stretch, and fluid shear stress generate changes in intracellular signaling and gene expression that contribute to the pathobiology of obstructive and nonobstructive kidney disease.