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

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 (PkdTKO) or both Pkd1 and Adamts1 (P/ATKO) using doxycycline induction at age 4-6 weeks. Uninduced (UI) mice were used as controls. Results: At 12 weeks age, P/ATKO mice showed less kidney enlargement than PkdTKO 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/ATKO kidneys, with IF localizing the cleaved versican to the TBM in PkdTKO 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/ATKO kidneys correlate with a significant reduction in peritubular macrophage accumulation compared to PkdTKO 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. Funding: Other U.S. Government SupportFig 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.