Role of Uromodulin in Early Fibrotic Remodeling During Sustained Crystal-Induced Kidney Injury

Background: Uromodulin(UMOD)plays complex and context-dependent roles in kidney pathophysiology.While protective in some acute injury models,its contribution to sustained tubulointerstitial damage—particularly in crystal nephropathy—remains unclear.This study investigates whether UMOD modifies sodium oxalate(NaOx)-induced renal injury and fibrotic responses over 30 days. Methods: Male C57BL/6 mice received a single intraperitoneal injection of:saline (control),UMOD(5µg/animal),NaOx(9mg/100g body weight),or NaOx+UMOD(uNaOx).After 30 days,animals were euthanized following24-hour metabolic cage housing.Two-way ANOVA analyzed results(mean ± SD)with Bonferroni post hoc tests or Welch’s test(GraphPad Prism;p<0.05 significant). Results: NaOx group showed increased kidney weight compared to controls (<0.0017).One week post-treatment,NaOx significantly increased food intake(<0.0176 vs. control)and urinary flow(<0.0139 vs. control).The uNaOx group showed increased food intake(<0.0026 vs.UMOD)but decreased urinary flow(p<0.0001 vs.NaOx;interaction p=0.0080).Urinary creatinine was higher in the uNaOx group vs.NaOx(<0.0001).Four weeks post-treatment,water intake was increased in the uNaOx group compared to NaOx alone(<0.0294).Urinary creatinine was reduced in the NaOx group vs. control(p<0.0068)and increased in the uNaOx vs.NaOx(p<0.0001;interaction p=0.0098).Serum creatinine was elevated in NaOx group vs.controls(<0.0125).Cortical injury score showed a significant interaction between factors (p=0.0082), with Welch’s test confirming increased injury in the NaOx vs.control (<0.0226).Medullary injury score also showed significant interaction (p=0.0261).Masson's trichrome staining did not reveal overt interstitial fibrosis, but intense luminal membrane staining was observed in proximal tubules,particularly in the NaOx group.Gene expression analysis showed significant upregulation of Col1a1 in the UMOD(p<0.0206),NaOx (<0.0152),and uNaOx(<0.0015)groups compared to the control.Col3a1 was significantly elevated in the uNaOx group vs.control (<0.0193), with a trend toward increase vs.NaOx (<0.0586). Conclusion: UMOD alone modestly upregulated fibrotic genes.Combined with NaOx,it amplified Col1a1 and Col3a1 expression,suggesting synergistic profibrotic signaling.Despite the absence of overt fibrosis,luminal matrix-like deposits and molecular changes indicate early fibrotic remodeling. Funding: Government Support – Non-U.S.