Adamts1 and Cyst Expansion in Polycystic Kidney Disease.

KEY POINTS: Adamts1 mRNA expression in the kidney was increased with loss of Pkd1, leading to cleavage of V1 isoform of versican in the tubular basement membrane. Increased versican cleavage promoted peritubular accumulation and activation of macrophages. Deletion of both Adamts1 and Pkd1 reduced versican cleavage, macrophage accumulation, and cyst growth and improved kidney function and survival. BACKGROUND: Autosomal dominant polycystic kidney disease is characterized by mutations in either the Pkd1 or Pkd2 genes, leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge after loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated. METHODS: Mice were generated with inducible tubule-specific knock-out of Adamts1 alone (Ats(TKO)), Pkd1 alone (Pkd(TKO)), or both (P/A(TKO)) after doxycycline induction from age 4 to 6 weeks. Uninduced mice were used as controls. Ats(TKO) mice had no detectable phenotype through age 12 weeks. RESULTS: Upregulation of Adamts1 in Pkd(TKO) kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubular basement membrane and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/A(TKO)) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/A(TKO) mice demonstrated reduced cystic enlargement, improved BUN and creatinine, and better survival than did Pkd(TKO) mice. CONCLUSIONS: Preventing Adamts1 upregulation after loss of tubular Pkd1 effectively reduced cyst growth and preserved kidney function.