PKD(inducible) Mice

Catalog Number: I001125

Strain Name: C57BL/6N;6JCya-Pkd1em1floxCdh16em1(IRES-MerCreMer)/Cya

Genetic Background: C57BL/6N;6JCya

 

Strain Description

Polycystin-1 (PC1), encoded by the PKD1 gene, is a large transmembrane glycoprotein that orchestrates critical cellular processes—including cell–cell and cell–matrix interactions, calcium signaling, and mechanosensation—in renal tubular epithelial cells. PC1 regulates diverse aspects of cellular function, such as signal transduction, cytoskeletal remodeling, and cell adhesion. It forms a functional complex with Polycystin-2 (PC2), the product of the PKD2 gene, to maintain intracellular calcium homeostasis and facilitate mechanotransduction [1]. Disruption of PC1 signaling, due to PKD1 mutations—which account for approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases—undermines these regulatory pathways, promoting abnormal cell proliferation and cyst formation [2]. Clinically, ADPKD is characterized by the progressive development of multiple fluid-filled cysts, renal enlargement, hypertension, and eventual progression to end-stage kidney disease (ESKD). With a global incidence estimated at 1 in 400 to 1 in 1000 individuals, ADPKD affects nearly 500,000 people in the United States alone and frequently involves extra-renal manifestations, including the heart, liver, pancreas, spleen, and arachnoid membrane [3]. Notably, genotypic heterogeneity exists, with PKD1 mutations often linked to an earlier onset and more aggressive disease course [2-3].

Traditional systemic Pkd1 knockout models are typically embryonically lethal, precluding long-term pathogenesis studies. In contrast, inducible, kidney-specific conditional knockout models using the Cre-LoxP system recapitulate the clinical features of human ADPKD and permit the investigation of disease progression in adult mice [4-5]. PKD(inducible) mice represent an inducible conditional Pkd1 knockout model generated by crossing Pkd1-floxed mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer). Offspring were induced with tamoxifen during lactation to achieve targeted deletion of Pkd1 within renal tubular epithelial cells. Preliminary observations at three weeks post-induction reveal pronounced polycystic kidney disease phenotypes, including the emergence of renal cysts, a marked increase in kidney volume, and elevated serum blood urea nitrogen (BUN) levels. We are continuing to monitor this model longitudinally to capture later-stage phenotypes and delineate the overall trajectory of disease progression.

Strain Strategy

The PKD(inducible) mouse model is generated by mating Pkd1-flox mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer, Catalog No.: C001432). Tamoxifen is administered during the lactation period to achieve renal-specific ablation of Pkd1. For further details regarding the Cdh16-MerCreMer strain, please consult the strain datasheet. The gene editing strategy employed for generating the Pkd1-flox allele is illustrated below.


Application

  • Calcium Homeostasis and Mechanotransduction.
  • Renal Tubular Biology.
  • ADPKD Modeling.
  • Broader Kidney Disease Research.

 

Validation Data

1. Kidney Cysts (3 and 6 Weeks Post-Induction)

Figure 1. Comparison of kidney morphology and weight in PKD(inducible) and control (Con) mice. Three and six weeks post-tamoxifen induction, kidneys from randomly selected mice were subjected to gross anatomical analysis, as depicted. At 3 weeks post-induction, all male PKD(inducible) mice exhibited a severe kidney cystic phenotype. Among female PKD(inducible) mice, 2 also presented with notable kidney cysts. Kidney weight analysis revealed a significant increase in the kidney-to-body weight ratio in male PKD(inducible) mice. Although female PKD(inducible) mice also showed a trend toward increased kidney-to-body weight ratio, the difference was not statistically significant (n = 3; data are presented as mean ± SEM). In mice randomly selected at 6 weeks post-induction, macroscopic kidney cysts were also observed in 2 male and 1 female PKD(inducible) mice. Collectively, these data indicate that this model exhibits a discernible ADPKD-like phenotype as early as 3 weeks post-tamoxifen induction.  Furthermore, there may be individual or sex-based variations in disease onset and severity, with male mice potentially exhibiting earlier onset or more severe disease. By week 6, the incidence rate in males was higher at 71% (5/7) compared to females at 33% (2/6) (n=3 at 3 weeks post-induction; n≥3 at 6 weeks post-induction; Bars represent mean ± SEM).

Genotype: PKD(inducible) mouse, Pkd1flox/flox;Cdh16IRES-MerCreMer/+. Control (Con) mouse, Pkd1flox/flox.

 

2. Blood Urea Nitrogen (BUN) and Creatinine (CREA)

Figure 2. Comparison of serum blood urea nitrogen (BUN) and creatinine (CREA) levels between PKD(inducible) mice and control (Con) mice. Serum biochemical analysis performed three weeks post-tamoxifen induction revealed significantly elevated BUN levels in male PKD(inducible) mice compared to controls, indicative of compromised renal function. In contrast, serum creatinine levels remained unchanged. In female PKD(inducible) mice, neither BUN nor creatinine levels showed significant differences relative to controls (n = 3; data are presented as mean ± SEM).

Genotype: PKD(inducible) mouse, Pkd1flox/flox;Cdh16IRES-MerCreMer/+. Control (Con) mouse, Pkd1flox/flox.

 

References
[1]Su Q, Hu F, Ge X, Lei J, Yu S, Wang T, Zhou Q, Mei C, Shi Y. Structure of the human PKD1-PKD2 complex. Science. 2018 Sep 7;361(6406):eaat9819.
[2]Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321-37.
[3]Mahboob M, Rout P, Leslie SW, et al. Autosomal Dominant Polycystic Kidney Disease. [Updated 2024 Mar 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan.
[4]Sieben CJ, Harris PC. Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing. Kidney360. 2023 Aug 1;4(8):1155-1173.
[5]Happé H, Peters DJ. Translational research in ADPKD: lessons from animal models. Nat Rev Nephrol. 2014 Oct;10(10):587-601.