N-acetylcysteine ameliorates hematuria-associated tubulointerstitial injury in 5/6 nephrectomy mice.

Abstract

Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.

• Authors: Ajay Medipally, Min Xiao, Anjali A Satoskar, Laura Biederman, Alana Dasgupta, Iouri Ivanov, Galina Mikhalina, Brad Rovin, Sergey V Brodsky
• Journal: Physiological reports (Physiol Rep) Vol. 11 Issue 13 Pg. e15767 (Jul 2023) ISSN: 2051-817X [Electronic] United States
• PMID: 37419616 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Acetylcysteine
• Warfarin
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha

Topics

• Humans
• Mice
• Rats
• Animals
• Acetylcysteine (pharmacology, therapeutic use)
• Warfarin (adverse effects)
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Mice, Inbred C57BL
• Kidney
• Nephrectomy
• Hematuria (etiology, chemically induced)
• Renal Insufficiency, Chronic (complications, drug therapy, chemically induced)
• Fibrosis