Adamts1 and Cyst Expansion in Polycystic Kidney Disease.
basic_science · Level V
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- Record sourced from PubMed, PMID 39514301.
- Also identified by DOI 10.1681/ASN.0000000557 and PMC identifier 11975248.
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Abstract
<i>Adamts1</i> 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 <i>Adamts1</i> and <i>Pkd1</i> reduced versican cleavage, macrophage accumulation, and cyst growth and improved kidney function and survival. Autosomal dominant polycystic kidney disease is characterized by mutations in either the <i>Pkd1</i> or <i>Pkd2</i> genes, leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge after loss of <i>Pkd1</i> without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of <i>Pkd1</i> null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (<i>Adamts1</i>) is the most highly expressed and upregulated. Mice were generated with inducible tubule-specific knock-out of <i>Adamts1</i> alone (Ats<sup>TKO</sup>), <i>Pkd1</i> alone (Pkd<sup>TKO</sup>), or both (P/A<sup>TKO</sup>) after doxycycline induction from age 4 to 6 weeks. Uninduced mice were used as controls. Ats<sup>TKO</sup> mice had no detectable phenotype through age 12 weeks. Upregulation of <i>Adamts1</i> in Pkd<sup>TKO</sup> 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 <i>Adamts1</i> and <i>Pkd1</i> (P/A<sup>TKO</sup>) reduced <i>Adamts1</i> expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/A<sup>TKO</sup> mice demonstrated reduced cystic enlargement, improved BUN and creatinine, and better survival than did Pkd<sup>TKO</sup> mice. Preventing <i>Adamts1</i> upregulation after loss of tubular <i>Pkd1</i> effectively reduced cyst growth and preserved kidney function.