Abstract
The aim of the study is to investigate the effects of pentoxifylline (PTX) on the renal tubular cell injury and stone formation in a hyperoxaluric rat model induced by ethylene glycol and its possible underlying mechanisms. The study was performed with 30 male Wistar rats and randomized into three groups of teen. The sham-control (group 1) received only drinking water orally. The EG/untreated (group 2) received drinking water containing 0.75% EG for 4 weeks orally. The EG/PTX treated (group 3) received drinking water containing 0.75% EG for 4 weeks orally and PTX. Urine and blood were collected to determine some parameters. The kidneys were also removed for histological examination. Serum and urinary parameters were significantly improved in the EG/PTX treated. In the EG/PTX-treated group, the MDA, TOS and MPO activity reduced and the TAS, SOD, CAT and GSH-Px activities were increased markedly compared with the group 2. In urine of the group 2 rats, a large number of CaOx crystals were displayed and most tubules that contained crystals were dilated and showed degeneration, necrosis, and desquamation of the lining epithelium. Only few CaOx crystals were r in EG/PTX-treated animal’s urine. Mild tissue damage was observed in PTX-treated rats. iNOS expression was significantly elevated in the group 2. In contrast, in the EG/PTX-treated group, eNOS expression in renal tubular epithelial cells was increased. Current study indicates that PTX may partially reduce renal tubular injury resulting from hyperoxaluria-induced oxidative and nitrosative stress.
Similar content being viewed by others
References
Daudon M, Jungers P (2004) Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Nephron Physiol 98:31–36
Gambaro G, Vezzoli G, Casari G, Rampoldi L, D’Angelo A, Borghi L (2004) Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 44:963–986
Coe FL, Parks JH, Asplin JR (1992) The pathogenesis and treatment of kidney stones. N Engl J Med 327:1141–1152
Tiselius HG (2000) Stone incidence and prevention. Braz J Urol 26:452–462
Thamilselvan S, Khan SR (1998) Oxalate and calcium oxalate crystals are injurious to renal epithelial cells: results of in vivo and in vitro studies. J Nephrol 11(Suppl 1):66–69
Bashir S, Gilani AH (2009) Antiurolithic effect of Bergenia ligulata rhizome: an explanation of the underlying mechanisms. J Ethnopharmacol 122:106–116
Thamilselvan S, Hackett RL, Khan SR (1997) Lipid peroxidation in ethylene glycol induced hyperoxaluria and calcium oxalate nephrolithiasis. J Urol 157:1059–1063
Thamilselvan S, Menon M (2005) Vitamin E therapy prevents hyperoxaluria-induced calcium oxalate crystal deposition in the kidney by improving renal tissue antioxidant status. BJU Int 96(1):117–126
Menon M, Koul H (1992) Clinical review 32: calcium oxalate nephrolithiasis. J Clin Endocrinol Metab 74:703–707
Liu D, Wang LN, Li HX, Huang P, Qu LB, Chen FY (2017) Pentoxifylline plus ACEIs/ARBs for proteinuria and kidney function in chronic kidney disease: a meta-analysis. J Int Med Res 45:383–398
Hashemi M (2014) The study of pentoxifylline drug effects on renal apoptosis and BCL-2 gene expression changes following ischemic reperfusion injury in rat. Iran J Pharm Res 13:181–189
Nasiri-Toosi Z, Dashti-Khavidaki S, Khalili H, Lessan-Pezeshki M (2013) A review of the potential protective effects of pentoxifylline against drug-induced nephrotoxicity. Eur J Clin Pharmacol 69:1057–1073
Atmani F, Slimani Y, Mimouni M, Hacht B (2003) Prophylaxis of calcium oxalate stones by Herniaria hirsuta on experimentally induced nephrolithiasis in rats. BJU Int 92:137–140
Li MG, Madappally MM (1989) Rapid enzymatic determination of urinary oxalate. Clin Chem 35:2330–2333
Yang X, Ding H, Qin Z et al (2016) Metformin prevents renal stone formation through an antioxidant mechanism in vitro and in vivo. Oxid Med Cell Longev 2016:4156075
Pareta SK, Patra KC, Mazumder PM, Sasmal D (2011) Aqueous extract of Boerhaavia diffusa root ameliorates ethylene glycol-induced hyperoxaluric oxidative stress and renal injury in rat kidney. Pharm Biol 49:1224–1233
Lee HJ, Jeong SJ, Lee HJ et al (2011) 1,2,3,4,6-Penta-O-galloyl-beta-d-glucose reduces renal crystallization and oxidative stress in a hyperoxaluric rat model. Kidney Int 79:538–545
Khan SR (2013) Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. J Urol 189:803–811
Thamilselvan S, Khan SR, Menon M (2003) Oxalate and calcium oxalate mediated free radical toxicity in renal epithelial cells: effect of antioxidants. Urol Res 31:3–9
Karadi RV, Gadge NB, Alagawadi KR, Savadi RV (2006) Effect of Moringa oleifera Lam. root-wood on ethylene glycol induced urolithiasis in rats. J Ethnopharmacol 105:306–311
Nizami AN, Rahman MA, Ahmed NU, Islam MS (2012) Whole leea macrophylla ethanolic extract normalizes kidney deposits and recovers renal impairments in an ethylene glycol-induced urolithiasis model of rats. Asian Pac J Trop Med 5:533–538
Selvam R, Kalaiselvi P, Govindaraj A, Murugan VB, Kumar AS (2001) Effect of A. lanatai leaf extract and Vediuppu chunnam on the urinary risk factors of calcium oxalate urolithiasis during experimental Hyperoxaluria. Pharmacol Res 43:89–93
Shukla AB, Mandavia DR, Barvaliya MJ, Baxi SN, Tripathi CR (2014) Evaluation of anti-urolithiatic effect of aqueous extract of Bryophyllum pinnatum (Lam.) leaves using ethylene glycol-induced renal calculi. Avicenna J Phytomed 4:151–159
McMartin K (2009) Are calcium oxalate crystals involved in the mechanism of acute renal failure in ethylene glycol poisoning? Clin Toxicol (Phila) 47: 859–869
Oksay T, Yunusoğlu S, Calapoğlu M, Aydın Candan I, Onaran İ, Ergün O, Özorak A (2017) Protective impact of resveratrol in experimental rat model of hyperoxaluria. Int Urol Nephrol 49:769–775
Vervaet BA, D’Haese PC, De Broe ME, Verhulst A (2009) Crystalluric and tubular epithelial parameters during the onset of intratubular nephrocalcinosis: illustration of the ‘fixed particle’ theory in vivo. Nephrol Dial Transplant 24:3659–3668
Nayeem K, Gupta D, Nayana H, Joshi RK (2010) Antiurolithiatic potential of the fruit extracts of Carica papaya on ethylene glycol induced urolithiatic rats. J Pharm Res 3:2772–2775
Robertson WG, Peacock M (1980) The cause of idiopathic calcium stone disease: hypercalciuria or hyperoxaluria? Nephron 26:105–110
Shukkur MF, Abdul SE, Devarajan A, Ramasamy S, Sethumadhvan S, Nachiappa GR et al (2005) Credential of Spirulina diet on stability and flux related properties on the biomineralization process during oxalate mediated renal calcification in rats. Clin Nutr 24:932–942
Ramesh C, John WE (2010) Antiurolithiatic activity of wood bark extracts of Cassia fistula in rats. JPBMS 2:1–9
Grases F, Genestar C, Conte A, March P, Costa-Bauza A (1989) Inhibitory effect of pyrophosphate, citrate, magnesium and chondroitin sulfate in calcium oxalate urolithiasis. Br J Urol 64:235–257
Francois B, Cahen R, Pascal B (1986) Inhibitors of urinary stone formation in 40 recurrent stone formers. Br J Urol 58:479–483
Chen YM, Lin SL, Chiang WC, Wu KD, Tsai TJ (2006) Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int 69:1410–1415
Ducloux D, Bresson-Vautrin C, Chalopin J (2001) Use of pentoxifylline in membranous nephropathy. Lancet 357:1672–1673
Khan SR (2014) Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl Androl Urol 3:256–276
Byer K, Khan SR (2005) Citrate provides protection against oxalate and calcium oxalate crystal induced oxidative damage to renal epithelium. J Urol 173:640–646
Miller C, Kennington L, Cooney R et al (2000) Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and necrosis. Toxicol Appl Pharmacol 162:132–141
Khand FD, Gordge MP, Robertson WG, Noronha-Dutra AA, Hothersall JS (2002) Mitochondrial superoxide production during oxalatemediated oxidative stress in renal epithelial cells. Free Radic Biol Med 32:1339–1350
Meimaridou E, Jacobson J, Seddon AM, Noronha-Dutra AA, Robertson WG, Hothersall JS (2005) Crystal and microparticle effects on MDCK cell superoxide production: oxalate-specific mitochondrial membrane potential changes. Free Radic Biol Med 38:1553–1564
Khan SR, Khan A, Byer KJ (2011) Temporal changes in the expression of mRNA of NADPH oxidase subunits in renal epithelial cells exposed to oxalate or calcium oxalate crystals. Nephrol Dial Transplant 26:1778–1785
Li N, Yi FX, Spurrier JL, Bobrowitz CA, Zou AP (2002) Production of superoxide through NADH oxidase in thick ascending limb of Henle’s loop in rat kidney. Am J Physiol Renal Physiol 282:F1111–F1119
Geiszt M, Kopp JB, Varnai P, Leto TL (2000) Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci USA 97:8010–8014
Zuo J, Khan A, Glenton PA, Khan SR (2011) Effect of NADPH oxidase inhibition on the expression of kidney injury molecule and calcium oxalate crystal deposition in hydroxy-l-proline-induced hyperoxaluria in the male Sprague-Dawley rats. Nephrol Dial Transplant 26:1785–1796
Aviado DM, Porter JM (1984) Pentoxifylline: a new drug for the treatment of intermittent claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy 4:297–307
Lai TS, Chiang WC, Chen YM (2016) Pentoxifylline: Evidence strong enough for renoprotection? J Formos Med Assoc 115:591–592
Lloris Carsi JM, Cejalvo Lapeña D, Toledo AH, Zaragoza Fernandez C, Toledo Pereyra LH (2013) Pentoxifylline protects the small intestine after severe ischemia and reperfusion. Exp Clin Transplant 11:250–258
Costantini TW, Deree J, Peterson CY, Putnam JG, Woon T, Loomis WH, Bansal V, Coimbra R (2010) Pentoxifylline modulates p47phox activation and downregulates neutrophil oxidative burst through PKA-dependent and -independent mechanisms. Immunopharmacol Immunotoxicol 32:82–91
Yang SK, Duan SB, Pan P, Xu XQ, Liu N, Xu J (2015) Preventive effect of pentoxifylline on contrast-induced acute kidney injury in hypercholesterolemic rats. Exp Ther Med 9:384–388
Lin SL, Chen YM, Chien CT, Chiang WC, Tsai CC, Tsai TJ (2002) Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol 13:2916–2929
Naghii MR, Jafari M, Mofid M, Eskandari E, Hedayati M, Khalagie K (2015) The efficacy of antioxidant therapy against oxidative stress and androgen rise in ethylene glycol induced nephrolithiasis in Wistar rats. Hum Exp Toxicol 34:744–754
Khan SR (2005) Hyperoxaluria-induced oxidative stress and antioxidants for renal protection. Urol Res 33:349–357
Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837
Buffoli B, Pechánová O, Kojsová 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
Hori K, Tsujii M, Iino T et al (2013) Protective effect of edaravone for tourniquet-induced ischemia-reperfusion injury on skeletal muscle in murine hindlimb. BMC Musculoskelet Disord 27:14:113
Wang W, Zolty E, Falk S, Basava V, Reznikov L, Schrier R (2006) Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291:F1090–F1095
Goligorsky MS, Brodsky SV, Noiri E (2002) Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int 61:855–861
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Ozturk, H., Cetinkaya, A., Firat, T.S. et al. Protective effect of pentoxifylline on oxidative renal cell injury associated with renal crystal formation in a hyperoxaluric rat model. Urolithiasis 47, 415–424 (2019). https://doi.org/10.1007/s00240-018-1072-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00240-018-1072-8