Loss of Inositol Polyphosphate-5-Phosphatase E in Adult Mouse Kidneys Causes Slow, Progressive Renal Cystogenesis

Background: Polycystic kidney disease (PKD) is a ciliopathy characterized by bilateral renal cysts leading to kidney failure. Genetic studies in patients and animal models show most PKD genes encode primary cilia proteins, underscoring their importance. However, the molecular mechanisms of cyst formation remain unclear, as does whether adult-onset ADPKD and early-onset ARPKD have different causes. INPP5E, a ciliary inositol polyphosphate 5-phosphatase, regulating phosphoinositides and proteins like Hedgehog pathway and various GPCRs, causes early-onset PKD when mutated biallelically, but its role in adult-onset PKD is unknown. Methods: We induced Inpp5e-inactivation in adult kidneys of Inpp5efl/fl; Pax8rtTA; tetO-Cre or Inpp5efl/fl; Pkd1RC/RC; Pax8rtTA; tetO-Cre mice by administering doxycycline in water at P28 for two weeks, using littermates drinking normal water as controls. Kidney cysts were monitored by MRI in live mice. Histological analyses were performed at endpoint based on body condition scoring. Results: After Dox treatment, Inpp5efl/fl; Pax8rtTA; tetO-Cre mice developed very mild kidney cysts by 6 months, progressing slowly to endpoint by 18 months. Histology showed cysts in collecting ducts with heavy fibrosis. Global AKT activity remained similar to normal at endpoint, and cilia appeared structurally normal in Inpp5e-null kidney tissues. Moreover, females progressed faster than males. Severe kidney cysts appeared just 1 week post-Dox in Inpp5efl/fl; Pkd1RC/RC; Pax8rtTA; tetO-Cre mice, while similar cysts appear in Pkd1RC/RC mice at 6 months. By 6-month, Inpp5e-/-; Pkd1RC/RC kidneys weighed >13-fold than Pkd1RC/RC. Monoallelic Inpp5e loss in adult Pkd1RC/RC kidneys also worsened PKD but less so. Total AKT activity was unchanged in both genotypes at endpoint. Conclusion: Unlike early-loss models, Inpp5e inactivation in adult mouse kidney causes very late-onset, slowly progressive PKD, distinct cystogenic mechanisms between embryonic and adult kidneys. INPP5E deficiency in mature renal tubules likely induces a very mild cystogenic signal, strongly amplified by hypomorphic Pkd1RC. Like polycystin-1, INPP5E dosage correlates with disease severity. The absence of global AKT changes suggests late-onset cystogenesis from Inpp5e loss is likely cilia-dependent. Funding: NIDDK Support, Other U.S. Government Support