Chondroitin Sulfate N‐Acetylgalactosaminyltransferase 1 Promotes the Progression of Renal Fibrosis Mediated by Versican 1 in Mouse Remnant Kidney

Renal fibrosis is a final common pathway for progressive chronic kidney diseases. Immune cell infiltration and production of tumour growth factor-β (TGF-β) are essential factors for fibrosis development. We examined the role of chondroitin sulfate (CS) proteoglycan, which is one of the main extracellular matrix components induced by TGF-β signalling. We also examined CS N-acetylgalactosaminyltransferase 1 (T1), an enzyme that catalyses the first step of CS-specific synthesis. T1-/- mice, genetically lacking T1, and T1+/+ mice underwent 5/6 nephrectomy (Nx) or sham operation. Kidney function, urine marker, mRNA expression, and TGF-β signalling were evaluated 1 month after Nx or sham operation. Renal fibrotic area was quantified 3 months later. Both T1+/+ and T1-/- mice with Nx showed equivalent loss of kidney function; however, a tubular damage marker, upregulation of TGF-β and collagen expression, and renal fibrosis were suppressed in T1-/- mice with Nx. Versican, one of the core proteins of CS proteoglycan, was exclusively upregulated in T1+/+ mice with Nx. Among the versican splicing variants, versican 1 (V1) was expressed in the medullary interstitium of the remnant kidney in T1+/+ mice. V1 was produced in the interstitial macrophages, fibroblasts/myofibroblasts, and endothelial cells, whereas TGF-β was expressed in fibroblasts/myofibroblasts. Phosphorylation of the TGF-β signalling molecules Smad2/3 was not induced in T1-/- mice with Nx. In vivo administration of TGF-β inhibitor into Nx mice reduced V1 and Tgfb expression. T1 was essential for effective TGF-β signalling, V1 upregulation, and subsequent renal fibrosis.