Inhibition of Hyaluronan Synthesis Attenuates Tubulointerstitial Inflammation and Fibrosis in Murine Unilateral Ureteral Obstruction Model of CKD

Background: Chronic kidney disease (CKD) is a major global issue resulting in considerable morbidity and mortality. Irrespective of the primary etiology, tubulo-interstitial fibrosis is the predominant pathogenic process in CKD progression to end-stage kidney disease, but the underlying mechanism remains obscure. Hyaluronan (HA) is a ubiquitous component of the extracellular matrix and is implicated in tissue inflammation and fibrosis. HA is synthesized by three enzymes, namely HA synthase (HAS), I, II and III. We investigated the roles of HAS I, II and III in tubulo-interstitial inflammation and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Methods: UUO or Sham operation (Control group) was performed on 10-week old male wild-type (WT) and HAS I, III or I/III knockout (KO) mice, and sacrificed 14 days after UUO and the kidneys were harvested to investigate histopathology and expression of mediators relating to inflammation, fibrosis and tubular injury. Results: Compared to WT Sham mice, WT mice with UUO showed increased tubulo-interstitial HA expression, and HAS I, II and III gene expression was increased by 360.70±82.95-fold, 91.91±14.6-fold and 3.96±0.37-fold respectively (p = 0.0020, <0.0001 and 0.0022 respectively). Increased HA expression was accompanied by tubular atrophy, immune cell infiltration, and increased expression of KIM-1, TNF-α, CCL-2, α-smooth muscle actin, fibronectin and collagen III (p<0.05, for all). HAS I, III and I/III KO mice with UUO showed reduced immune cell infiltration, tubular atrophy and mediators of renal tubular injury, inflammation and fibrosis, and reduced HA expression, compared to WT UUO mice. HAS I KO was associated with more marked reduction in the expression of inflammatory and fibrotic mediators. Conclusion: Our findings suggest that HA and HAS I, II, and III may have distinct roles in mediating tubulo-interstitial inflammation and fibrosis in murine UUO CKD model. Funding: Government Support – Non-U.S.