Abstract: SA-PO0620
Early Phenotype in Umod-Associated Autosomal Dominant Tubulointerstitial Kidney Disease Knockin Mice
Session Information
- Monogenic Kidney Diseases: Tubular and Other
November 08, 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
- Riedhammer, Korbinian M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States
- Lemberg, Katharina, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States
- Kolvenbach, Caroline Maria, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States
- Sayer, John Andrew, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States
- Lomjansook, Kraisoon, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Saida, Ken, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Franken, Gijs AC, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Marchuk, Daniel, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Zion, Elena, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Nelson, Becca, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Prakash, Chiranth M, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Buerger, Florian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background
UMOD-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) is a slowly progressive inherited kidney disease leading to kidney failure (KF) in adulthood. It is caused by heterozygous pathogenic variants in UMOD resulting in deposition of misfolded UMOD in the endoplasmic reticulum (ER) causing ER stress, cell death, and kidney fibrosis. UMOD is nearly exclusively expressed in the thick ascending limb of Henle’s loop (TAL).
We investigated early disease manifestations in an ADTKD-Umod knock-in mouse model under the hypothesis that ER retention begins as soon as TAL cells have developed.
Methods
A knock-in mouse model, carrying the pathogenic Umod variant C125R, was used (PMID: 28325753). Phenotyping was done in male/female mice at ages two weeks to six months by immunofluorescence microscopy of kidney sections, qPCR and Western blot from whole-kidney lysates, and measurement of urinary NGAL (distal tubular injury marker).
Results
ER-retention of UMOD was already visible at age 2 weeks in heterozygous, and, more noticeably, in homozygous mice compared to wild-type (WT) mice. Mutant UMOD colocalized with the ER marker calnexin, while WT UMOD had a cytoplasmic/apical distribution. Urinary NGAL was significantly increased in one-month-old homozygous mice, and also in heterozygotes in the course of six months. Mediators of the unfolded protein response (e.g., GRP78) were also found significantly elevated in mutant mice by age six months. Likewise, expression of ER-stress-induced Casp12 was significantly upregulated in homozygous mice by two months and also upregulated by six months of age in heterozygotes and homozygotes.
Conclusion
ADTKD-UMOD is an inherited kidney disease leading to KF in adult life. Although no approved causative treatment exists, there is a recent therapeutic breakthrough involving an investigational small molecule rectifying trafficking of misfolded UMOD and ameliorating disease sequelae in vivo (PMID: 39680459). However, these studies were performed in nine to ten months old, male-only mice. Here, we show that pathologic phenotypes are present as early as 2 weeks of age in Umod mutant mice of both sexes, which could constitute a rationale for early targeted treatment, e.g., by oligonucleotide-based knockdown.