Kidney Week

Abstract: SA-PO816

Phenotypic Quantification of an Hnf1b Knockout Mouse Model

Session Information

• Genetic Diseases: Glomerulopathies - II
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Hölzel, Selina, Boston Children's Hospital, Boston, Massachusetts, United States

Selina Hölzel,

• Kolvenbach, Caroline Maria, Boston Children's Hospital, Boston, Massachusetts, United States

Caroline Maria Kolvenbach,

• Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States

Florian Buerger,

• Lemberg, Katharina, Boston Children's Hospital, Boston, Massachusetts, United States

Katharina Lemberg,

• Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States

Ken Saida,

• Yu, Seyoung, Boston Children's Hospital, Boston, Massachusetts, United States

Seyoung Yu,

• Salmanullah, Daanya, Boston Children's Hospital, Boston, Massachusetts, United States

Daanya Salmanullah,

• Mansour, Bshara, Boston Children's Hospital, Boston, Massachusetts, United States

Bshara Mansour,

• Elmubarak, Izzeldin, Boston Children's Hospital, Boston, Massachusetts, United States

Izzeldin Elmubarak,

• Mertens, Nils David, Boston Children's Hospital, Boston, Massachusetts, United States

Nils David Mertens,

• Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States

Shirlee Shril,

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) constitute the most frequent birth defect and are the leading cause of chronic kidney disease in the first three decades of life. Approximately 50 monogenic genes, if mutated, are known to cause CAKUT, explaining 5–20% of disease origin. Mutations in the transcription factor HNF1B represent the most common monogenic cause of CAKUT in 5% up to 30% of affected patients. To date, prevention and treatment options for patients with CAKUT are limited. To enable gene replacement therapy (GRT) for CAKUT, we re-phenotyped a published conditional Hnf1b knockout mouse model (Gresh EMBO J 7:1657-68, 2004) and developed an additional quantifiable phenotyping method to generate reproducible reference for evaluation of future GRT effects.

Methods

Kidney specific Hnf1b inactivation is achieved by usage of the Cre-LoxP technology under a kidney specific promoter (KspCre). We utilized a colony of heterozygous breeder pairs (Hnf1b^flox/+, KspCre+, C57BL/6J) and phenotypically evaluated mutant animals (Hnf1b^flox/flox, KspCre+) compared to heterozygous littermate controls starting at P0. For quantitative analyses we focused on the following independent parameters, adapted to Gresh et al.: Kaplan-Meier survival, weight gain over time, macroscopic and light microscopic examination of kidney and urinary tract.

Results

83.3% (n=6) of mutant mice died before weaning with survival rates ranging from 1-12 days (median 9 days). Mutant mice living past P5 (n=2) showed growth retardation and an average weight reduction of 41% compared to controls. Macroscopically, we observed ureteral dilatation in 100% and hydronephrosis in 33.3% of mutant animals (n=3). Upon light microscopy we detected and quantified renal tubular cysts in equatorial kidney sections with an average of 129 cysts in mutant animals (n=3) and 0 cysts in controls (n=3).

Conclusion

We performed quantitative phenotype evaluation of a kidney specific Hnf1b knockout mouse model (Gresh et al.) providing reference for future in vivo mouse studies aiming for treatment of CAKUT.

Funding

• NIDDK Support