Kidney Week

Abstract: FR-PO605

Tubule-Specific Deletion of Adamts1 Slows Cyst Expansion in Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | 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: Cystic

Authors

• Kakade, Vijayakumar R., Yale University, New Haven, Connecticut, United States

Vijayakumar R. Kakade, PhD

• Akman, Zafer, Yale University, New Haven, Connecticut, United States

Zafer Akman, MD

• Motrapu, Manga, Yale University, New Haven, Connecticut, United States

Manga Motrapu

• Cantley, Lloyd G., Yale University, New Haven, Connecticut, United States

Lloyd G. Cantley, MD, FASN

Background

Autosomal dominant polycystic kidney disease is caused by mutations in either the PKD1 or PKD2 genes leading to cyst growth. We have shown that with loss of Pkd1 the tubules can enlarge without an increase in tubular cell numbers, suggesting that tubular basement membrane (TBM) remodeling is important for cystic dilation. Bulk RNAseq and qPCR analysis of metalloproteinases showed that A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) expressed by proximal tubule is the most significantly upregulated metalloproteinase following loss of Pkd1 expression. We now show that Adamts1 promotes cyst growth following Pkd1 loss.

Methods

Mice were developed with inducible tubule-specific knockout of Pkd1 alone (Pkd^TKO) or both Pkd1 and Adamts1 (P/A^TKO) using doxycycline induction at age 4-6 weeks. Uninduced (UI) mice were used as controls.

Results

At 12 weeks age, P/A^TKO mice showed less kidney enlargement than Pkd^TKO mice (KW/BW ratio 0.009±0.003 vs 0.017±0.01 respectively, p<0.05) and a lower cyst index (29.1±7.2 vs 44.2±6.1 respectively, p<0.01) (Fig 1). Western blot showed a 2.5-fold increase in the 70kDa V1 neoepitope of the Adamts1 cleavage substrate versican that was prevented in P/A^TKO kidneys, with IF localizing the cleaved versican to the TBM in Pkd^TKO kidneys (Fig 2). The 70kDa cleaved versican, named versikine, has been shown to activate macrophage. Our data confirm that the decreased versikine levels in P/A^TKO kidneys correlate with a significant reduction in peritubular macrophage accumulation compared to Pkd^TKO kidneys.

Conclusion

Adamts1 is upregulated with the loss of Pkd1 expression, resulting in versican cleavage in the TBM with enhanced cyst formation and accelerated loss of kidney function.

Fig 1. Deletion of Adamts1 slows cyst growth. (A) Kidney weight; (B) kidney weight to body weight ratio; (C) H&E images and (F) Cyst index.

Fig 2. Adamts1 cleaved versican in the TBM. (A) IF staining for V0V1 neoepitope. (B) Mean fluorescence intensity.

Funding

• Other U.S. Government Support