XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1Mutation in Mice

XBP1 activation in neonatal and adult doxycycline-inducible murine models of ADPKD due to a hypomorphic polycystin-1 missense mutation orthologous to human PC1R2220W delays cyst formation. Activating XBP1s, a pro-chaperone inducer of the endoplasmic reticulum stress response, can improve steady-state expression, ciliary trafficking, and cleavage of the mutant protein, providing initial in vivoproof of concept that modulating levels of poorly functioning hypomorphic PC1 alleles can slow progression of kidney cyst formation in ADPKD.