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Reno-protective effects of ursodeoxycholic acid against gentamicin-induced nephrotoxicity through modulation of NF-κB, eNOS and caspase-3 expressions


Gentamicin (GNT) is a potent aminoglycoside antibiotic widely used to treat life-threatening bacterial infections. We aim to investigate the potential protective effect of ursodeoxycholic acid (UDCA) against GNT-induced nephrotoxicity. In this study, 24 male Wistar rats were used and randomly divided into four groups of six animals each. Control group received 0.5% carboxymethyl cellulose orally for 15 days, GNT group received GNT 100 mg/kg/day i.p. for 8 days, UDCA group received UDCA orally for 15 consecutive days at a dose of 60 mg/kg/day suspended in 0.5% carboxymethyl cellulose and UDCA-pretreated group received UDCA orally for 7 days then co-administered with GNT i.p. for 8 days at the same fore-mentioned doses. Serum levels of kidney function parameters (urea, creatinine, uric acid and albumin) were measured. Renal tissues were used to evaluate oxidative stress markers; malonaldehyde (MDA), reduced glutathione (GSH) and the anti-oxidant enzyme superoxide dismutase (SOD) activities and nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and kidney injury molecule-1 (KIM-1) mRNA levels. Immunohistochemical expression of endothelial nitric oxide synthase (eNOS) and caspase-3 and histological and ultrastructural examination were performed. Treatment with GNT increased the serum levels of renal function parameters and renal MDA, NF-κB and KIM-1 mRNA levels, while it decreased GSH and SOD activities. Marked immunohistochemical expression of caspase-3 was observed after GNT administration while it decreased eNOS expression. Histological and ultrastructural alterations were also evident in renal corpuscles and tubules. In contrast, pretreatment with UDCA reversed changes caused by GNT administration. These results suggest that UDCA ameliorates GNT-induced kidney injury via inhibition of oxidative stress, inflammation and apoptosis.

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  1. Abdel-Raheem IT, Abdel-Ghany AA, Mohamed GA (2009) Protective effect of quercetin against gentamicin-induced nephrotoxicity in rats. Biol Pharm Bull 32:61–67

  2. Adil M, Kandhare AD, Dalvi G, Ghosh P, Venkata S, Raygude KS, Bodhankar SL (2016) Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Ren Fail 38:996–1006

  3. Akao Y, Maruyama W, Shimizu S, Yi H, Nakagawa Y, Shamoto-Nagai M, Youdim MB, Tsujimoto Y, Naoi M (2002) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. J Neurochem 82:913–923

  4. Akbulut S, Elbe H, Eris C, Dogan Z, Toprak G, Yalcin E, Otan E, Turkoz Y (2015) Effects of antioxidant agents against cyclosporine-induced hepatotoxicity. J Surg Res 193:658–666

  5. Akcay A, Nguyen Q, Edelstein CL (2009) Mediators of inflammation in acute kidney injury. Mediat Inflamm 2009:137072

  6. Amaral JD, Castro RE, Sola S, Steer CJ, Rodrigues CM (2007) p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem 282:34250–34259

  7. Appel GB (1990) Aminoglycoside nephrotoxicity. Am J Med 88:16S–20S

  8. Araujo M, Welch WJ (2006) Oxidative stress and nitric oxide in kidney function. Curr Opin Nephrol Hypertens 15:72–77

  9. Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U (2005) Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 30:245–252

  10. Bae EH, Kim IJ, Joo SY, Kim EY, Choi JS, Kim CS, Ma SK, Lee J, Kim SW (2014) Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats. J Renin-Angiotensin-Aldosterone Syst 15:348–361

  11. Balakumar P, Rohilla A, Thangathirupathi A (2010) Gentamicin-induced nephrotoxicity: do we have a promising therapeutic approach to blunt it? Pharmacol Res 62:179–186

  12. Baliga R, Ueda N, Walker PD, Shah SV (1999) Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 31:971–997

  13. Bartels H, Bohmer M, Heierli C (1972) Serum creatinine determination without protein precipitation. Clin Chim Acta 37:193–197

  14. Baum N, Dichoso CC, Carlton CE (1975) Blood urea nitrogen and serum creatinine. Physiology and interpretations. Urology 5:583–588

  15. Bledsoe G, Crickman S, Mao J, Xia CF, Murakami H, Chao L, Chao J (2006) Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. Nephrol Dial Transplant 21:624–633

  16. Bozzola JJ (1998) Electron microscopy: principles and techniques for biologists, Second edn. Jones and Bartlett Publishers, Inc., USA

  17. Buffoli B, Pechanova O, Kojsova S, Andriantsitohaina R, Giugno L, Bianchi R, Rezzani R (2005) Provinol prevents CsA-induced nephrotoxicity by reducing reactive oxygen species, iNOS, and NF-kB expression. J Histochem Cytochem 53:1459–1468

  18. Burne MJ, Elghandour A, Haq M, Saba SR, Norman J, Condon T, Bennett F, Rabb H (2001) IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury. J Leukoc Biol 70:192–198

  19. Buryova H, Chalupsky K, Zbodakova O, Kanchev I, Jirouskova M, Gregor M, Sedlacek R (2013) Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity. BMC Gastroenterol 13:155

  20. Cao A, Wang L, Chen X, Guo H, Chu S, Zhang X, Peng W (2016a) Ursodeoxycholic acid ameliorated diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress. Biol Pharm Bull 39:1300–1308

  21. Cao AL, Wang L, Chen X, Wang YM, Guo HJ, Chu S, Liu C, Zhang XM, Peng W (2016b) Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy. Lab Investig 96:610–622

  22. Chen Q, Cui Y, Ding G, Jia Z, Zhang Y, Zhang A, Huang S (2017) PEA3 protects against gentamicin nephrotoxicity: role of mitochondrial dysfunction. Am J Transl Res 9:2153–2162

  23. Chen X, Xu J, Zhang C, Yu T, Wang H, Zhao M, Duan ZH, Zhang Y, Xu JM, Xu DX (2011) The protective effects of ursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice. Eur J Pharmacol 659:53–60

  24. Chun HS, Low WC (2012) Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells. Toxicology 292:105–112

  25. Cui S, Verroust PJ, Moestrup SK, Christensen EI (1996) Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Phys 271:F900–F907

  26. Davies J, Davis BD (1968) Misreading of ribonucleic acid code words induced by aminoglycoside antibiotics. The effect of drug concentration. J Biol Chem 243:3312–3316

  27. de-Barros-e-Silva ML, Varanda WA, Lachat JJ, Alves-da-Silva CG, Coimbra TM (1992) Glomerular permeability to macromolecules in gentamicin-treated rats. Braz J Med Biol Res 25:409–417

  28. Drury RAB, Wallington EA (1980) Carleton's histological technique, 5th edn. Oxford University Press, Oxford, New York, Toronto

  29. Dumas BT, Watson WA, Biggs HG (1997) Albumin standards and the measurement of serum albumin with bromcresol green. Clin Chim Acta 258:21–30

  30. Edson RS, Terrell CL (1999) The aminoglycosides. Mayo Clin Proc 74:519–528

  31. El Mouedden M, Laurent G, Mingeot-Leclercq MP, Taper HS, Cumps J, Tulkens PM (2000) Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides. Antimicrob Agents Chemother 44:665–675

  32. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

  33. Erdem A, Gundogan NU, Usubutun A, Kilinc K, Erdem SR, Kara A, Bozkurt A (2000) The protective effect of taurine against gentamicin-induced acute tubular necrosis in rats. Nephrol Dial Transplant 15:1175–1182

  34. Fawcett JK, Scott JE (1960) A rapid and precise method for the determination of urea. J Clin Pathol 13:156–159

  35. Furusu A, Miyazaki M, Abe K, Tsukasaki S, Shioshita K, Sasaki O, Miyazaki K, Ozono Y, Koji T, Harada T, Sakai H, Kohno S (1998) Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int 53:1760–1768

  36. Ghaznavi R, Kadkhodaee M (2007) Comparative effects of selective and non-selective nitric oxide synthase inhibition in gentamicin-induced rat nephrotoxicity. Arch Toxicol 81:453–457

  37. Giurgea-Marion L, Toubeau G, Laurent G, Heuson-Stiennon JA, Tulkens PM (1986) Impairment of lysosome-pinocytic vesicle fusion in rat kidney proximal tubules after treatment with gentamicin at low doses. Toxicol Appl Pharmacol 86:271–285

  38. Gorriz JL, Martinez-Castelao A (2012) Proteinuria: detection and role in native renal disease progression. Transplant Rev (Orlando) 26:3–13

  39. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244

  40. Hosaka EM, Santos OF, Seguro AC, Vattimo MF (2004) Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats. Braz J Med Biol Res 37:979–985

  41. Ikari A, Nagatani Y, Tsukimoto M, Harada H, Miwa M, Takagi K (2005) Sodium-dependent glucose transporter reduces peroxynitrite and cell injury caused by cisplatin in renal tubular epithelial cells. Biochim Biophys Acta 1717:109–117

  42. Ikegami T, Matsuzaki Y (2008) Ursodeoxycholic acid: mechanism of action and novel clinical applications. Hepatol Res 38:123–131

  43. Jia P, Teng J, Zou J, Fang Y, Jiang S, Yu X, Kriegel AJ, Liang M, Ding X (2013) Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity. PLoS One 8:e64329

  44. Jiang X, Wang X (2004) Cytochrome C-mediated apoptosis. Annu Rev Biochem 73:87–106

  45. Jose SP, A S, K IM, R M, Santhosh S, S S, K GB, P C (2017) Nephro-protective effect of a novel formulation of unopened coconut inflorescence sap powder on gentamicin induced renal damage by modulating oxidative stress and inflammatory markers. Biomed Pharmacother 85:128–135

  46. Juan SH, Chen CH, Hsu YH, Hou CC, Chen TH, Lin H, Chu YL, Sue YM (2007) Tetramethylpyrazine protects rat renal tubular cell apoptosis induced by gentamicin. Nephrol Dial Transplant 22:732–739

  47. Kalayarasan S, Prabhu PN, Sriram N, Manikandan R, Arumugam M, Sudhandiran G (2009) Diallyl sulfide enhances antioxidants and inhibits inflammation through the activation of Nrf2 against gentamicin-induced nephrotoxicity in Wistar rats. Eur J Pharmacol 606:162–171

  48. Ko WK, Kim SJ, Jo MJ, Choi H, Lee D, Kwon IK, Lee SH, Han IB, Sohn S (2018) Ursodeoxycholic acid inhibits inflammatory responses and promotes functional recovery after spinal cord injury in rats. Mol Neurobiol

  49. Ko WK, Lee SH, Kim SJ, Jo MJ, Kumar H, Han IB, Sohn S (2017) Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide-stimulated inflammatory responses in RAW 264.7 macrophages. PLoS One 12:e0180673

  50. Kumari A, Kakkar P (2012) Lupeol prevents acetaminophen-induced in vivo hepatotoxicity by altering the Bax/Bcl-2 and oxidative stress-mediated mitochondrial signaling cascade. Life Sci 90:561–570

  51. Kurihara N, Yanagisawa H, Sato M, Tien CK, Wada O (2002) Increased renal vascular resistance in zinc-deficient rats: role of nitric oxide and superoxide. Clin Exp Pharmacol Physiol 29:1096–1104

  52. Lapenna D, Ciofani G, Festi D, Neri M, Pierdomenico SD, Giamberardino MA, Cuccurullo F (2002) Antioxidant properties of ursodeoxycholic acid. Biochem Pharmacol 64:1661–1667

  53. Laurent G, Kishore BK, Tulkens PM (1990) Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 40:2383–2392

  54. Lee IC, Kim SH, Lee SM, Baek HS, Moon C, Kim SH, Park SC, Kim HC, Kim JC (2012) Melatonin attenuates gentamicin-induced nephrotoxicity and oxidative stress in rats. Arch Toxicol 86:1527–1536

  55. Lee KE, Kim EY, Kim CS, Choi JS, Bae EH, Ma SK, Kim KK, Lee JU, Kim SW (2013) Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells. Biochem Biophys Res Commun 434:527–533

  56. Li J, Li L, Wang S, Zhang C, Zheng L, Jia Y, Xu M, Zhu T, Zhang Y, Rong R (2018) Resveratrol alleviates inflammatory responses and oxidative stress in rat kidney ischemia-reperfusion injury and H2O2-induced NRK-52E cells via the Nrf2/TLR4/NF-kappaB pathway. Cell Physiol Biochem 45:1677–1689

  57. Linas SL, Shanley PF, Whittenburg D, Berger E, Repine JE (1988) Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Phys 255:F728–F735

  58. Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ (2011) New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 79:33–45

  59. Luft FC, Yum MN, Walker PD, Kleit SA (1977) Gentamicin gradient patterns and morphological changes in human kidneys. Nephron 18:167–174

  60. Luo QH, Chen ML, Chen ZL, Huang C, Cheng AC, Fang J, Tang L, Geng Y (2016) Evaluation of KIM-1 and NGAL as early indicators for assessment of gentamycin-induced nephrotoxicity in vivo and in vitro. Kidney Blood Press Res 41:911–918

  61. Maldonado PD, Barrera D, Medina-Campos ON, Hernandez-Pando R, Ibarra-Rubio ME, Pedraza-Chaverri J (2003) Aged garlic extract attenuates gentamicin induced renal damage and oxidative stress in rats. Life Sci 73:2543–2556

  62. Manktelow A, Meyer AA (1986) Lack of correlation between decreased chemotaxis and susceptibility to infection in burned rats. J Trauma 26:143–148

  63. Marklund SL (1985) Superoxide dismutase isoenzymes in tissues and plasma from New Zealand black mice, nude mice and normal BALB/c mice. Mutat Res 148:129–134

  64. Mihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278

  65. Mitsuyoshi H, Nakashima T, Sumida Y, Yoh T, Nakajima Y, Ishikawa H, Inaba K, Sakamoto Y, Okanoue T, Kashima K (1999) Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun 263:537–542

  66. Montogomery HAC, Dymock JF (1961) The determination of nitrite in water: colorimetric method of nitric oxide assay. Analyst 86:414

  67. Morales AI, Detaille D, Prieto M, Puente A, Briones E, Arevalo M, Leverve X, Lopez-Novoa JM, El-Mir MY (2010) Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int 77:861–869

  68. Morsy MA, Ibrahim SA, Amin EF, Kamel MY, Rifaai RA, Hassan MK (2014) Sildenafil ameliorates gentamicin-induced nephrotoxicity in rats: role of iNOS and eNOS. J Toxicol 2014:489382

  69. Nagai J, Saito M, Adachi Y, Yumoto R, Takano M (2006) Inhibition of gentamicin binding to rat renal brush-border membrane by megalin ligands and basic peptides. J Control Release 112:43–50

  70. Nagai J, Takano M (2004) Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet 19:159–170

  71. Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, Goto N, Takeda K, Utsunomiya H, Oda K, Warabi E, Ishii T, Osaka K, Hyodo I, Yamamoto M (2008) Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Am J Physiol Gastrointest Liver Physiol 295:G735–G747

  72. Osorio H, Coronel I, Arellano A, Franco M, Escalante B, Bautista R (2012) Ursodeoxycholic acid decreases sodium-glucose cotransporter (SGLT2) expression and oxidative stress in the kidney of diabetic rats. Diabetes Res Clin Pract 97:276–282

  73. Otunctemur A, Ozbek E, Cekmen M, Cakir SS, Dursun M, Polat EC, Somay A, Ozbay N (2013) Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Ren Fail 35:403–410

  74. Ou HC, Lee WJ, Lee SD, Huang CY, Chiu TH, Tsai KL, Hsu WC, Sheu WH (2010) Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. Toxicol Appl Pharmacol 248:134–143

  75. Ozbek E, Cekmen M, Ilbey YO, Simsek A, Polat EC, Somay A (2009) Atorvastatin prevents gentamicin-induced renal damage in rats through the inhibition of p38-MAPK and NF-kappaB pathways. Ren Fail 31:382–392

  76. Padanilam BJ (2003) Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis. Am J Physiol Renal Physiol 284:F608–F627

  77. Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, Darley-Usmar VM (1999) Biological aspects of reactive nitrogen species. Biochim Biophys Acta 1411:385–400

  78. Pattyn VM, Verpooten GA, Giuliano RA, Zheng F, De Broe ME (1988) Effect of hyperfiltration, proteinuria and diabetes mellitus on the uptake kinetics of gentamicin in the kidney cortex of rats. J Pharmacol Exp Ther 244:694–698

  79. Perez MJ, Macias RI, Marin JJ (2006) Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta 27:34–41

  80. Polat A, Parlakpinar H, Tasdemir S, Colak C, Vardi N, Ucar M, Emre MH, Acet A (2006) Protective role of aminoguanidine on gentamicin-induced acute renal failure in rats. Acta Histochem 108:365–371

  81. Poupon R (2012) Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol 36(Suppl 1):S3–S12

  82. Priuska EM, Schacht J (1995) Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem Pharmacol 50:1749–1752

  83. Promsan S, Jaikumkao K, Pongchaidecha A, Chattipakorn N, Chatsudthipong V, Arjinajarn P, Pompimon W, Lungkaphin A (2016) Pinocembrin attenuates gentamicin-induced nephrotoxicity in rats. Can J Physiol Pharmacol 94:808–818

  84. Quiros Y, Blanco-Gozalo V, Sanchez-Gallego JI, Lopez-Hernandez FJ, Ruiz J, Perez de Obanos MP, Lopez-Novoa JM (2016) Cardiotrophin-1 therapy prevents gentamicin-induced nephrotoxicity in rats. Pharmacol Res 107:137–146

  85. Quiros Y, Vicente-Vicente L, Morales AI, Lopez-Novoa JM, Lopez-Hernandez FJ (2011) An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin. Toxicol Sci 119:245–256

  86. Radermacher J, Klanke B, Schurek HJ, Stolte HF, Frolich JC (1992) Importance of NO/EDRF for glomerular and tubular function: studies in the isolated perfused rat kidney. Kidney Int 41:1549–1559

  87. Raij L, Baylis C (1995) Glomerular actions of nitric oxide. Kidney Int 48:20–32

  88. Ramesh G, Reeves WB (2002) TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110:835–842

  89. Rodrigues CM, Fan G, Wong PY, Kren BT, Steer CJ (1998) Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med 4:165–178

  90. Sahu BD, Kalvala AK, Koneru M, Mahesh KJ, Kuncha M, Rachamalla SS, Sistla R (2014a) Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-kappaB activation and antioxidant defence. PLoS One 9:e105070

  91. Sahu BD, Tatireddy S, Koneru M, Borkar RM, Kumar JM, Kuncha M, Srinivas R, Shyam SR, Sistla R (2014b) Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection. Toxicol Appl Pharmacol 277:8–20

  92. Sandoval RM, Molitoris BA (2004) Gentamicin traffics retrograde through the secretory pathway and is released in the cytosol via the endoplasmic reticulum. Am J Physiol Renal Physiol 286:F617–F624

  93. Sardana A, Kalra S, Khanna D, Balakumar P (2015) Nephroprotective effect of catechin on gentamicin-induced experimental nephrotoxicity. Clin Exp Nephrol 19:178–184

  94. Schrier RW, Wang W, Poole B, Mitra A (2004) Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114:5–14

  95. Selby NM, Shaw S, Woodier N, Fluck RJ, Kolhe NV (2009) Gentamicin-associated acute kidney injury. QJM 102:873–880

  96. Sepand MR, Ghahremani MH, Razavi-Azarkhiavi K, Aghsami M, Rajabi J, Keshavarz-Bahaghighat H, Soodi M (2016) Ellagic acid confers protection against gentamicin-induced oxidative damage, mitochondrial dysfunction and apoptosis-related nephrotoxicity. J Pharm Pharmacol 68:1222–1232

  97. Shi KQ, Fan YC, Liu WY, Li LF, Chen YP, Zheng MH (2012) Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis. Mol Biol Rep 39:9715–9722

  98. Shin HS, Yu M, Kim M, Choi HS, Kang DH (2014) Renoprotective effect of red ginseng in gentamicin-induced acute kidney injury. Lab Investig 94:1147–1160

  99. Stambe C, Atkins RC, Tesch GH, Kapoun AM, Hill PA, Schreiner GF, Nikolic-Paterson DJ (2003) Blockade of p38alpha MAPK ameliorates acute inflammatory renal injury in rat anti-GBM glomerulonephritis. J Am Soc Nephrol 14:338–351

  100. Sun J, Hultenby K, Axelsson J, Nordstrom J, He B, Wernerson A, Lindstrom K (2017) Proximal tubular expression patterns of megalin and cubilin in proteinuric nephropathies. Kidney Int Rep 2:721–732

  101. Tang WW, Feng L, Mathison JC, Wilson CB (1994) Cytokine expression, upregulation of intercellular adhesion molecule-1, and leukocyte infiltration in experimental tubulointerstitial nephritis. Lab Investig 70:631–638

  102. Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV (2006) Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 290:F517–F529

  103. Volpini RA, Costa RS, da Silva CG, Coimbra TM (2004) Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. Nephron Physiol 98:97–106

  104. Ward JBJ, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ni GJ, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ (2017) Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312:G550–G558

  105. Watanabe A, Nagai J, Adachi Y, Katsube T, Kitahara Y, Murakami T, Takano M (2004) Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists. J Control Release 95:423–433

  106. Whiting PH, Brown PA (1996) The relationship between enzymuria and kidney enzyme activities in experimental gentamicin nephrotoxicity. Ren Fail 18:899–909

  107. Yanagida C, Ito K, Komiya I, Horie T (2004) Protective effect of fosfomycin on gentamicin-induced lipid peroxidation of rat renal tissue. Chem Biol Interact 148:139–147

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The authors would like to thank Dr. Adel Maklad from the College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA, for reviewing the language of the manuscript.

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Correspondence to Tarek Hamdy Abd-Elhamid.

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Abd-Elhamid, T.H., Elgamal, D.A., Ali, S.S. et al. Reno-protective effects of ursodeoxycholic acid against gentamicin-induced nephrotoxicity through modulation of NF-κB, eNOS and caspase-3 expressions. Cell Tissue Res 374, 367–387 (2018).

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  • Ursodeoxycholic acid
  • Gentamicin
  • NF-κB
  • eNOS
  • Caspase-3