Table 3.

NAC protective effects in animal models of kidney disease

Pathology	Animal model	NAC concentration/ administration way	Time points and scheme of administration	Kidney effects	Other effects	Ref.
Nephrotoxicity and obstructive nephropathy	Folic acid (2–28 d)	300 mg/kg intragastric	2 doses, 24 and 2 h before renal damage induction	↓ Serum BUN and creatinine and kidney weight/total rat weight ↓ Renal injured and fibrotic area, necrotic tubules number ↓ Renal vascular resistance ↑ GFR and renal blood flow ↓ Lipoperoxidation markers ↑ PGC-1α and TFAM levels ↓ NOX and NOS ROS production in proximal and distal tubule. ↑ LC3-II, LC3-I and PINK levels.	↑ Mitochondrial glutathione total and reduced levels ↑ Mitochondrial complex I and III activities ↑ Mitochondrial β-oxidation ↓ Mitochondrial ROS production ↑ Mitochondrial ATP production and coupling ↑ Prevent mitochondrial membrane potential (Δψm) depolarization. Prevent the shift of mitochondrial dynamics towards fission Preserve mitochondria ultrastructure	Aparicio-Trejo et al.,49 Aparicio-Trejo et al.50
Nephrotoxicity	Cisplatin (8–12 wk)	500 mg/kg intragastric	From 7 d prior to cisplatin up to 12 wk (every 2 d).	↓ Serum BUN and creatinine Prevent premature renal senescence ↓ p53 and p21 protein and IL-6, IL-1β, fibronectin, αSMA and TNFα mRNA levels ↓ Fibrosis	↑ Sirt1 levels	Li et al.47
Nephrotoxicity	CdCl2	0.4 mg/l in drinking water for 1 mo	For 1 mo before CdCl2	↓ Serum BUN and creatinine ↓ SABG-positive areas ↓ The expression of senescence proteins and ↑ cell proliferation ↓ α-SMA, collagen I, MMP2, and TGF-β mRNA levels and renal fibrosis ↑ Sirt1 and PGC-1α levels ↓ Apoptosis in tubular cells	Preserve mitochondria ultrastructure ↑ UCP2, ATP5A, TFAM, NRF1, PGC-1α, and PGC-1β mRNA levels	Dong et al.57
Renal mass reduction and lipotoxicity	Human VSMCs treated with serum from left nephrectomy and ApoE-/- mice with high fat diet.	5000 μmol/l	pre-incubated by 1 h before serum treatment	↓ Serum BUN and creatinine	↓ ROS levels, p38-MAPK activation, lamin B1 and p53 levels in HVSMCs ↓ SABG staining in HVSMCs	Wang et al.48
Polycystic kidney disease	Cy/+ rats (autosomal dominant mutation in Anks6 gene)	80 mg/kg	5 wk	↓ phosphorus, TBARS and ↑ calcium serum levels	↓ Total bone levels of AGE	Allen et al.52
Renal Ischemia	20 min of I/R after a 21-d evolution of bilateral IR.	5% in normal powdered chow 300 mg/kg intraperitoneal	1 wk before bilateral IR and for 21 d after IR 4 h before the operation and at the beginning of reperfusion	↓ Tubular epithelial apoptosis and ↑ HO-1 in acute stage ↑ Apoptosis and 8-OhdG positive cells, and ↑ NADH fluorescence in the cortex in CKD stage ↓ BUN and creatinine ↑ SOD and GP× activities ↓ Renal MDA, interstitial inflammation and nitrate/nitrite rate	↓ Aspartate aminotransferase in serum	Small et al.28 Kizilgun et al.51
Renal mass reduction	5/6 nephrectomy 5/6 nephrectomy plus gadolinium-chelate	80 mg/kg in drinking water 600 mg/l in drinking water 4.8 g/l in drinking water	Orally in drinking water at 3, 8, or 19 wk after nephrectomy During 60 d after 7 d of nephrectomy From d 7 after nephrectomy to d 21 From d 60 after nephrectomy to d 120 2 d before gadolinium	Delay of systolic blood pressure increase ↓ Urea, creatinine, total cholesterol and triglyceride levels in plasma and systolic blood pressure ↓ Total AGE and TBARS ↑ Mean body weight and inulin clearance. ↓ Proteinuria, urinary TBARS excretion, blood pressure, fraction of potassium expression, urinary sodium/ potassium ratio, Serum aldosterone and glomerulosclerosis index ↓ Proteinuria, Prevention of the glomerular filtration decrease	↓ Endoplasmic reticulum stress proteins: Grp78, Grp94 and PDI. ↓ Apo A-I-mediated cholesterol efflux and ABCA-1 levels in Macrophages. ↓ Heart weight ↓ Serum ferritin and transferring saturation levels	Ware et al.64 Machado et al.58 Pereira et al.,45 Shimizu et al.59
Nephrotoxicity	Vancomycin-induced nephrotoxicity	10 or 30 mg/kg intraperitoneal	8 d starting 1 d before vancomycin	↓ BUN and creatinine levels, and interstitial edema and inflammatory cell infiltration. ↓ KIM-1, NGAL, Bax and caspase-3 and BCL2 ↑ expression. ↓ MDA and ↑GSH levels, ↑ SOD and CAT activities.	↓P38-MAPK and JNK phosphorylation.	Yu et al.61
Obstructive nephropathy	Unilateral ureteral obstruction (UUO)	250 mg/kg intraperitoneal	7 d	↓ Fibronectin, collagen I α-SMA and TGF-β fibrotic marker and ROS levels and angiotensin-II pathway		Shen et al.55
Contrast-induced nephropathy	Contrast-induced nephropathy	150 mg/kg intraperitoneal	For 4 consecutive d	↓ Serum BUN, creatinine, cystatin-C, N-acetyl-β-glucosaminidase and urinary γ-glutamyl transpeptidase levels. ↓ Tubular epithelial cell apoptosis, swelling of mitochondria, fracture of cristae, and shedding of microvilli of cell cavity. Preserved SOD activity, MDA and GSH levels,	Prevented p38-MAPK and ASK1 activation and ↑ Trx1 mRNA and protein levels.	Gong et al.46
Nephrotoxicity	Lithium chloride	10 mg/kg Intraperitoneal	Twice daily/5 wk	↓ BUN and creatinine in plasma and tubular necrosis ↑ GFR		Efrati et al.43
Uremic toxin associated renal disease	Bisphenol A (BPA)	100 mg/kg intragastric 200 mg/kg intragastric	Daily for 4 wk after BPA induced CKD Daily for 5 wk	↓ BUN, creatinine, proteinuria, apoptotic cells in proximal tubule and podocyte structure damage ↑ Creatinine clearance. ↓ Nitric oxide and MDA levels, Bax/Bcl-2 ratio and caspase activation Restore GSH balance and SOD activity ↑ p-AMPK/AMPK ratio, PGC-1α and Sirt3 levels and ↓ Ac-SOD2/SOD2 ratio ↓ BUN, glomerular and tubular damage ↓ Nitric oxide, MDA and NF-κB levels and NOS-immunostaining ↑ GSH, IL-4, Nrf2	↓ Mitochondria swollen, fragmentation and cristae disruption and ROS production ↑ Mitochondria number Restore Δψm	Kobroob et al.56 Abdelrazik et al.63
Nephrotoxicity	Ifosfamide	1.2 g/kg intraperitoneal	Daily for 6 d before IFO Daily for 3 d after IFO	Prevent IFO-induced Nephrotoxicity measured by BUN and creatinine levels	Did not affect IFO tumor growth inhibition	Hanly et al.44

8-OhdG, 8-hydroxy-2' -deoxyguanosine; ABCA-1, ATP-binding cassette transporter-1; Grp94, heat shock protein 90kDa beta member 1; Grp78, 78 kDa glucose-regulated protein; AGE, advanced glycation end products; AMPK, AMP-activated protein kinase; Apo A-I, apolipoprotein A-I; ApoE, apolipoprotein E; ASK1, apoptosis signal-regulating kinase 1; ATP, adenosine triphosphate; ATP5α, ATP synthase F1 subunit alpha; Bax, Bcl-2 associated X-protein; Bcl2, B-cell lymphoma 2; BPA, bisphenol A; BUN, blood urea nitrogen; CaO×, calcium oxalate; CAT, catalase; CdCl₂, cadmium chloride; CKD, chronic kidney disease; GFR, glomerular filtration rate; GPx, glutathione peroxidase; GSH, glutathione; HO-1, heme oxigenase; I/R, ischemia-reperfusion; IFO, Ifosfamide; IL-4, interleukin-4; IL-6, interleukin-6; IL-1β, interleukin-1-beta; JNK, c-Jun N-terminal kinases; KIM-1, kidney injury molecule 1; LC3 (I and II), Microtubule-associated protein 1A/1B-light chain 3 I and II; (p38)-MAPK, (p38) mitogen-activated protein kinases; MDA, malondialdehyde; MMP2, matrix metallopeptidase 2; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide reduced; NF-κB, Nuclear factor kappa B; NGAL, neutrophil gelatinase associated lipocalin; NOS, nitric oxide synthases; NOX, NADPH oxidase; NRF1, nuclear respiratory factor 1; Nrf2, nuclear factor erythroid 2–related factor 2; p53, tumor suppressor P53; PDI, protein disulfide isomerase; PGC-1 (α and β), peroxisome proliferator-activated receptor-gamma coactivator; PINK, phosphatase and tensin homologue-induced kinase 1; ROS, reactive oxygen species; SABG, senescence-associated beta-galactosidase; Sirt1, sirtuin 1; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances; TFAM, mitochondrial transcription factor A; TGF-β, transforming growth factor-beta; TNFα, tumor necrosis factor alpha; Trx1, thioredoxin 1; UCP2, uncoupling protein 2; αSMA, alpha smooth muscle actin; Δψm, mitochondrial membrane potential; VSMCs, vascular smooth muscle cells.