Kidney Week

Abstract: FR-PO0075

Distinct Renal Cyst Progression Occurs Depending on Depletion Timing in an Ift140 Conditional Knockout Mouse Model

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Yang, Hana, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Hana Yang, PhD

• Mann, Zoey, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Zoey Mann, MS

• Kennedy, Kristian M., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Kristian M. Kennedy

• Sohi, Gurparneet Kaur, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Gurparneet Kaur Sohi, MBBS

• Sieben, Cynthia J., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Cynthia J. Sieben, PhD

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

Peter C. Harris, PhD

Group or Team Name

• Robert M. and Billie Kelley Pirnie Translational Polycystic Kidney Disease Center

Background

ADPKD is a common genetic disease, often causing kidney failure due to mutations in PKD1 (~81%), PKD2 (~15%), and IFT140 (~2%). The ADPKD-IFT140 phenotype features fewer, larger cysts, while biallelic mutations cause syndromic ciliopathies. IFT140 is the largest intraflagellar transport protein (IFT), essential for the formation and function of primary cilia; however, the pathomechanisms underlying ADPKD-IFT140 remain unclear.

Methods

An inducible conditional mouse model (Ift140^flox/flox; Pax8-rtTA+; (tetO)7-Cre+) allowed kidney tubule-specific Ift140 knockout (cKO) at different timepoints. Doxycycline (dox) was administered to pregnant dams via food at embryonic day (E) 14.5 or to the mother/pups at postnatal day (P) 7 via food or intraperitoneal (IP) injection. Mice were monitored by MRI and total kidney volume (TKV) measured for up to 1.5 years (yrs) or until animals expired. Semi-quantitative (sq) PCR was performed to assess cre-recombination efficiency, and histology used to evaluate post-mortem kidney phenotypes. Cilia loss and cyst origin were also determined by immunofluorescence imaging.

Results

When Ift140 was deleted at E14.5 (via food), severe PKD (significantly increased TKV) was observed at 1 month (m) with lethality before 2m. In contrast, P7 loss (via food/mother’s milk) did not induce MRI-visible cysts by 1m, but medullary dilation was evident by 3m, cortical cysts by ~9m, and florid cysts by 1.5 yrs. SqPCR showed that cre-recombination was comparable between E14.5 and P7. Cyst origin analyses indicated involvement of both proximal tubules and collecting ducts. P7 IP cKO mice showed more rapid progression than oral dox, with cilia loss and mild dilation by 1m, but not the dramatic cystic disease seen in the E14.5 cKO mice.

Conclusion

The markedly milder cyst development associated with Ift140 loss at P7 vs. E14.5 contrasts with the later developmental shift from severe to mild disease observed in Pkd1 (~P13) or Ift88 (~P12) mouse models, suggesting different cilial/functional impacts. However, the timing and ciliary structure/protein trafficking consequence of Ift140 loss in vivo still needs to be assessed. Whether IFT140 reduction during the critical embryonic window or later accounts for the few, large cysts in ADPKD-IFT140 and the milder phenotype than ADPKD-PKD1 remains unclear.

Funding

• NIDDK Support