Chitosan Prevents Gentamicin-Induced Nephrotoxicity via a Carbonyl Stress-Dependent Pathway

Abstract

Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC) has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day) or metformin (100 mg/kg/day) was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM), a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days). Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp., P < 0.05). Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp., P < 0.05). Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway.

Accumulation of methylglyoxal and d‐lactate in Pb‐induced nephrotoxicity in rats

“…In addition, an increase in the concentration of AGEs is also found in patients with Alzheimer's disease (Ahmed et al ., ). Our previous reports reveal that either aristolochic acid or gentamicin‐induced renal injury is related to the accumulation of MG (Li et al, ; Li, Shih, & Lee, ; Huang, Chen, Li, & Lee, ; Chou, Chen, Li, Huang, & Lee, ; Chou, Li, Chen, Shih, & Lee, ). The glyoxalase system (GLO) plays a vital role in detoxifying reactive MG. MG consumes GSH to transform S ‐ d ‐lactoyl‐glutathione using GLO1 and subsequently transforms to d ‐lactate by GLO2 (McKinney & Gocke, ) as shown in Figure .…”

Evolving Evidence of Methylglyoxal and Dicarbonyl Stress Related Diseases from Diabetic to Non-Diabetic Models

“…The AGEs in renal tissue are also present in AAN mice [13]. Low-molecular-weight chitosan is a known MGO-chelating agent, established by in vitro and in vivo experiments [14]. In an AAN mouse model, administration of low-molecular-weight chitosan after aristolochic acid exposure mitigates renal accumulation of MGO and AGE, reverses glutathione depletion, and prevents further renal failure [15].…”

“…A previous study finds accumulation of MGO and AGEs in renal tissue accompanied with overt renal failure within 1 week following aminoglycoside exposure in mice [16]. Using low-molecular-weight chitosan also reverses MGO and AGE increases and prevents further renal dysfunction [14]. Metformin is used as anti-diabetic agent and is approved by US Food and Drug Administration as an MGO lowering agent [9].…”

“…More studies are required to understand the role of MGO in progression of renal failure in different kind of model. Low-molecular-weight chitosan, a MGO chelating agent, is efficacious in mouse models of diabetes [49], AN, and AAN [14,15]. Study of non-diabetic nephropathy helps us understand carbonyl stress in alternative modes of renal failure and devise potential treatments.…”

“…They are well-known contributors to the development of diabetic complications. Recently, dicarbonyl stress has been established as a pathogenesis factor in diseases other than diabetes, such as renal failure [13][14][15][16][17], hypertension [18,19], and sepsis [20]. These diseases present normal blood sugar, yet they share some features with diabetes.…”