N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder

Abstract

Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD.

The impact of advanced glycation end products on bone properties in chronic kidney disease

“…Additionally, antioxidant therapy with N-acetylcysteine (NAC) has been used in CKD patients to reduce oxidative stress and is hypothesized to reduce the downstream formation of AGEs. Interestingly, NAC did not alter oxidative stress markers but did reduce bone AGE content in Cy/ þ rats, as determined by a fluorescent AGE assay [55]. HPLC measurements did not indicate changes in skeletal pentosidine levels, and bone mechanical properties failed to improve.…”

N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients—focus on the antioxidant and anti-inflammatory properties

“…In other in vivo studies, NAC appeared to have a protective effect on cyclosporin induced nephrotoxicity, through amelioration of local and systemic OS [ 80 ]. Experimental studies also suggested another molecular pathway through which NAC combats OS; in uremic animals, NAC administration directly attacked and neutralized AGEs that are released due to the uremic environment [ 81 ].…”

N‐acetyl‐L‐cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress

“…21 Moreover, some publications indicated that NAC also helped prevent kidney or neurologic damage caused by some drugs. 22,23 NAC also possesses the ability to improve insulin resistance and T2DM. 7 Previous study has revealed that NAC could attenuate GDM by reducing DNA methylation in HepG2 cells.…”

“…NAC was also reported to protect patients against acute liver failure, 20 especially acetaminophen‐caused liver injury and acute liver failure 21 . Moreover, some publications indicated that NAC also helped prevent kidney or neurologic damage caused by some drugs 22,23 . NAC also possesses the ability to improve insulin resistance and T2DM 7 .…”