Preliminary Data: Inducible PKD Mouse Model Shows Phenotype in as Fast as 3 Weeks

ADPKD is the most common inherited kidney disorder worldwide and a major cause of end-stage kidney disease (ESKD). Its hallmark pathology involves progressive renal cyst formation, primarily due to mutations in the PKD1 gene. The development of robust animal models has been critical for elucidating ADPKD mechanisms, but early models were limited by embryonic lethality or insufficient disease phenotypes.

Cyagen has developed a novel tamoxifen-inducible, kidney-specific Pkd1 knockout mouse model, delivering clear ADPKD-like phenotypes in as little as three weeks post-induction. This article presents an overview of the disease background, model construction, and key phenotypic data.

Learn more about Cyagen's PKD (inducible) mouse model

Global Population Incidence & Pathology of ADPKD

As the most common hereditary kidney disease, ADPKD affects more than 12 million people worldwide and is one of the leading causes of end-stage kidney disease (ESKD).^[3–4] It is estimated that the global incidence of ADPKD is approximately 1 in every 400 to 1,000 individuals. In China, there are an estimated 1.25 million patients, while the United States has around 500,000 cases. Incidence rates may vary across different ethnic groups.^[4–5]

The disease pathology is primarily characterized by the progressive development of bilateral renal cysts, leading to kidney enlargement and declining renal function. Many patients eventually require dialysis or kidney transplantation.^[1]

Figure 1. Disease progression of autosomal dominant polycystic kidney disease (ADPKD).^[2]

PKD1 Mutation: The Primary Cause of ADPKD

ADPKD is primarily caused by autosomal dominant mutations in the PKD1 gene, meaning that the loss or mutation of a single copy is sufficient to cause disease. More than 80% of ADPKD cases are attributed to mutations in the PKD1 gene.^[6]

The PKD1-encoded polycystin-1 (PC1) protein interacts with PKD2-encoded polycystin-2 (PC2) protein to form a complex. This complex plays a crucial role in regulating intracellular calcium homeostasis and mechanosensory signaling, both of which are essential for maintaining the structure and function of renal tubules.^[7] Mutations in PKD1 disrupt PC1 function, thereby impairing normal cellular and ciliary signaling pathways, and leading to abnormal cell proliferation and cyst formation.^[8]

Figure 2. PKD1 mutation is the primary genetic cause of ADPKD.^[8]

PKD1 Gene Mutations and ADPKD Pathology

Mutations in the PKD1 gene exhibit high heterogeneity and include a variety of mutation types, such as truncating mutations (e.g., frameshift and nonsense mutations) and non-truncating mutations (e.g., missense and splice-site mutations). The type of mutation present can generally be associated with the severity of disease pathology as follows:

• Truncating mutations in PKD1 (e.g., nonsense or frameshift mutations) are associated with earlier and more severe disease onset.
• Non-truncating mutations (e.g., missense or splice-site mutations) and PKD2 mutations are typically linked with milder phenotypes.^[9–11]

Inducible Conditional Pkd1 Knockout Mice: The Ideal Choice for ADPKD Research

Mouse models are indispensable tools in the study of autosomal dominant polycystic kidney disease (ADPKD), with PKD1-related models being a major focus of research. Early systemic PKD1 knockout mouse models were critical for understanding the role of PKD1, but they also had notable limitations:

• Homozygous Pkd1 knockout mice exhibit embryonic lethality.
• Heterozygous mice present with mild, late-onset phenotypes that do not accurately mimic the progressive nature of human ADPKD.^[12–13]

To overcome these limitations, researchers have developed a range of conditionally inducible PKD1 knockout mouse models. These models enable gene inactivation at specific developmental stages or in adulthood, allowing precise temporal and spatial control of disease onset, thus better recapitulating the progression of ADPKD. For example, the Cre-LoxP recombinase system can be used to induce PKD1 inactivation at specific stages or in targeted tissues to circumvent the issue of embryonic lethality in standard PKD1 knockout mice.

Under the control of tamoxifen-inducible, kidney-specific Cre recombinase, PKD1 can be selectively knocked out in renal tissues, minimizing systemic effects and providing a controllable research platform for studying the intrinsic mechanisms of ADPKD and evaluating potential therapies.^[13–14] These advanced models are essential for the preclinical assessment of novel therapeutic interventions for ADPKD.

Figure 3. Inducible Kidney-Specific Pkd1 Knockout Mice Provide a More Suitable Model for ADPKD Research. ^[14]

Cyagen Inducible PKD Mouse Model: Key Features

Model Name: PKD (inducible) mouse
Product No.: I001225
Genotype: Pkd1-flox × Cdh16-MerCreMer (Product No.: C001432)
Induction Method: Tamoxifen during the nursing period

Cyagen’s independently developed PKD (Inducible) Mouse Model (Product No.: I001225) is an inducible, conditional Pkd1 knockout model. It is generated by crossing Pkd1-flox mice with tamoxifen-inducible, kidney-specific Cre-expressing mice (Cdh16-MerCreMer, Product No.: C001432), followed by tamoxifen induction during the nursing period of the offspring.

The Cdh16-MerCreMer transgene restricts Cre recombinase activity to renal tissue, and tamoxifen allows temporal control. This enables researchers to precisely induce Pkd1 deletion in the kidney, providing a more physiologically relevant model for ADPKD.

Early-Onset ADPKD Phenotypes: Preliminary Data

Preliminary data show that as early as three weeks after tamoxifen induction, a subset of mice exhibit pronounced ADPKD phenotypes. These include renal cyst formation, significant kidney enlargement, and elevated levels of blood urea nitrogen (BUN).

The following presents the preliminary phenotypic data of this model.

1. Renal Cyst Formation & Kidney Enlargement

To assess renal changes, a subset of mice was randomly selected for kidney dissection and weight measurement at 3 and 6 weeks post-tamoxifen induction. The results showed that PKD (inducible) mice exhibited clear ADPKD-like phenotypes as early as 3 weeks after induction, with significant sex- and individual-based variability observed.

During the 6-week observation period, male PKD (inducible) mice showed a higher incidence of cystic kidney disease compared to females (71% vs. 33%), and potentially more severe disease progression.

Figure 4. Comparison of Kidney Morphology and Weight Between PKD (Inducible) Mice and Control (Con) Mice.

2. Renal Function Assessment: BUN and Creatinine

To assess kidney function, serum biochemical analysis was performed on a subset of mice randomly selected 3 weeks after tamoxifen induction.

Serum biochemical testing at 3 weeks revealed:

• Significantly elevated blood urea nitrogen (BUN) in male PKD (inducible) mice, indicating renal impairment.
• Creatinine (CREA) levels remained statistically unchanged at this stage.
• No significant changes in BUN or CREA were observed in female mice at this time point.

Figure 5. Comparison of Serum Blood Urea Nitrogen (BUN) and Creatinine (CREA) Levels Between PKD (Inducible) Mice and Control (Con) Mice.

Conditional Inducible PKD Mouse Model Summary

The PKD (inducible) mouse model (Product No.: I001225) is an inducible conditional Pkd1 knockout model generated by breeding Pkd1-flox mice with tamoxifen-inducible, kidney-specific Cre driver mice (Cdh16-MerCreMer, Product No.: C001432). This model demonstrates a high capacity to mimic disease progression. Data show that as early as three weeks after tamoxifen induction, a subset of mice exhibited significant polycystic kidney disease (PKD) phenotypes, including renal cyst formation, marked kidney enlargement, and elevated serum blood urea nitrogen (BUN) levels.

These preliminary findings indicate that the PKD (inducible) mouse model effectively replicates early-onset, severe ADPKD-like phenotypes in humans, providing a powerful tool for in-depth investigation of ADPKD pathogenesis and therapeutic strategies. Cyagen’s inducible PKD mouse model provides a flexible and scalable platform for:

• Investigating ADPKD molecular mechanisms
• Performing preclinical evaluation of candidate therapies
• Studying early-stage disease progression under controlled experimental conditions

Going forward, we will continue long-term monitoring of this model to fully characterize the late-stage phenotypic progression and overall disease course. Further pathological analysis will be conducted to deliver more comprehensive data support for related research.

Cyagen’s Broader Portfolio in Metabolic Disease Modeling

In addition to ADPKD models, Cyagen provides a wide range of metabolic and cardiovascular disease mouse models for drug discovery and translational research. Our collaborations span biotech firms, pharmaceutical companies, and academic institutions globally.

We have established a variety of metabolic disease models to support both disease mechanism studies and new drug development, including:

• Liver disease models
• Obesity and diabetes models
• Hyperuricemia models
• Atherosclerosis models

To learn more, view the list below or visit our Metabolic Disease Models page.

Gene Edited Models for Metabolic and Cardiovascular Disease Research

Other Models for Metabolic and Cardiovascular Disease Research: Spontaneous, Induced, Composite, & Surgical Models

References
[1]Leslie SW, et al. Autosomal Dominant Polycystic Kidney Disease. [Updated 2024 Mar 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan.
[2]Steele C, Nowak K. Obesity, Weight Loss, Lifestyle Interventions, and Autosomal Dominant Polycystic Kidney Disease. Kidney Dial. 2022 Mar;2(1):106-122.
[3]Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321-37.Mahboob M, Rout P,
[4]Kidney Disease: Improving Global Outcomes (KDIGO) ADPKD Work Group. KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Kidney Int. 2025 Feb;107(2S):S1-S239.
[5]Mei CL, Xue C, Yu SQ, Dai B, Chen JH, Li Y, Chen LM, Liu ZS, Wu YG, Hu Z, Zha Y, Liu H, Zhuang YZ, Zhang C, Xiao XC, Wang Y, Li GS, Ma YY, Li L. Executive Summary: Clinical Practice Guideline for Autosomal Dominant Polycystic Kidney Disease in China. Kidney Dis (Basel). 2020 May;6(3):144-149.
[6]Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, Eckloff BW, Ward CJ, Winearls CG, Torres VE, Harris PC. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33.
[7]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.
[8]Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Primers. 2018 Dec 6;4(1):50.
[9]Cornec-Le Gall E, Audrézet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, Charasse C, Whebe B, Renaudineau E, Jousset P, Guillodo MP, Grall-Jezequel A, Saliou P, Férec C, Le Meur Y. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13.
[10]Rossetti S, Burton S, Strmecki L, Pond GR, San Millán JL, Zerres K, Barratt TM, Ozen S, Torres VE, Bergstralh EJ, Winearls CG, Harris PC. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol. 2002 May;13(5):1230-7.
[11]Leonhard WN, Happe H, Peters DJ. Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context. J Am Soc Nephrol. 2016 Dec;27(12):3530-3538.
[12]Takakura A, Contrino L, Beck AW, Zhou J. Pkd1 inactivation induced in adulthood produces focal cystic disease. J Am Soc Nephrol. 2008 Dec;19(12):2351-63.
[13]Happé H, Peters DJ. Translational research in ADPKD: lessons from animal models. Nat Rev Nephrol. 2014 Oct;10(10):587-601.
[14]Sieben CJ, Harris PC. Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing. Kidney360. 2023 Aug 1;4(8):1155-1173.