Kidney Week

Abstract: FR-PO0669

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

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Chen, Chuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Chuan Chen, PhD

• Gao, Yue, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Yue Gao, MD

• Ji, Biyun, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Biyun Ji, APN

• Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jinghua Hu, PhD

• Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Ling, Kun, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Kun Ling, PhD

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 Inpp5e^fl/fl; Pax8^rtTA; tetO-Cre or Inpp5e^fl/fl; Pkd1^RC/RC; Pax8^rtTA; 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, Inpp5e^fl/fl; Pax8^rtTA; 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 Inpp5e^fl/fl; Pkd1^RC/RC; Pax8^rtTA; tetO-Cre mice, while similar cysts appear in Pkd1^RC/RC mice at 6 months. By 6-month, Inpp5e^-/-; Pkd1^RC/RC kidneys weighed >13-fold than Pkd1^RC/RC. Monoallelic Inpp5e loss in adult Pkd1^RC/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 Pkd1^RC. 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

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025a1pcm698