Impact of nanoparticle albumin-bound paclitaxel on microscopic structure and immunohistochemical expression of transforming growth factor-β1 in the renal cortex of rat diabetic nephropathy

Shireen A. Mazroa, Samar A. Asker


Background: Diabetic nephropathy is a serious complication of diabetes. A low dose of paclitaxel drug ameliorates fibrosis in different diseases. Nano-particle albumin–bound paclitaxel (nab-paclitaxel) is a novel formula of paclitaxel approved in many countries.

Methods:This study aimed to investigate the effect of nab-paclitaxel on microscopic structure and immunohistochemical expression of transforming growth factor-β1 (as a fibrogenic mediator) in the renal cortex of rat diabetic nephropathy. Forty five adult rats were divided into; group I (control), group II (receiving nab-paclitaxel), group III (diabetic) and group IV (diabetic rats receiving nab-paclitaxel). After 4 weeks, kidneys were prepared for light microscopy and TGF- β1 immunohistochemical study.

Results: Renal cortex in group II had a microscopic structure similar to group I. TGF- β1 immune-reaction was negative in group I and II. Group III showed microscopic diabetic changes as hypertrophied renal corpuscles, expanded mesangial matrix, degenerated tubules, interstitial inflammatory cells infiltration, and glomerular and tubulo-interstitial fibrosis. A positive TGF- β1 immune-reaction was detected in renal corpuscles and tubules. In group IV, diabetic changes were relatively ameliorated with decreased TGF-β1immune-expression.

Conclusions:Nab-paclitaxel partially ameliorated microscopic structural changes in renal cortex of rats with diabetic nephropathy and decreased TGF-β1 immune-expression, suggesting a partial reno-protective effect of nab-paclitaxel in diabetic nephropathy.


Diabetic nephropathy, immunohistochemistry, Light microscopy, Nab-paclitaxel, Renal cortex, TGF-β1

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Gray S, Cooper M. Diabetic nephropathy in 2010: Alleviating the burden of diabetic nephropathy. Nat Rev Nephrol. 2011;7(2):71-3.

Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol. 2007;27(2):195-207.

Hills C, Squires P. TGF-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol. 2010;31:68-74.

Srivastava S, Koya D, Kanasaki K. MicroRNAs in kidney fibrosis and diabetic nephropathy: roles on EMT and EndMT. Biomed Res Int. 2013:125469.

Dai C, Liu Y: Hepatocyte growth factor antagonizes the profibrotic action of TGF-β1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J Am Soc Nephrol. 2004;15:1402-12.

Zhou J, Zhong D, Wang Q, Miao X, Xu X. Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-β/Smad activity. World J Gasteroenterol. 2010;16 (26):3330-4.

Zhang D, Yang, R, Wang S, Dong Z. Paclitaxel: new uses for an old drug. Drug Des Devel Ther. 2014;20(8):279-84.

Khanna C, Rosenberg M, Vail D. A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs. J Vet Intern Med. 2015;29(4):1006-12.

Stinchcombe T. Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of paclitaxel. Nanomedicine (Lond). 2007;2(4):415-23.

Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A. et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317-24.

Gradishar W. Albumin-bound paclitaxel: a next-generation taxane. Expert Opinion on Pharmacotherapy. 2006;7(8):1041-53.

Liu X, Zhu S, Wang T, Hummers L, Wigley F, Goldschmidt-Clermont P. et al. Paclitaxel modulates TGF-β signaling in scleroderma skin grafts in immunodeficient mice. PLoS Med. 2005;2(12):e354

Grube E, Dawkins K, Guagliumi G, Banning A, Zmudka K, Colombo A, et al. TAXUS VI final 5-year results: a multicentre, randomised trial comparing polymer-based moderate-release paclitaxel-eluting stent with a bare metal stent for treatment of long, complex coronary artery lesions. EuroIntervention. 2009;4(5):572-7.

Hellal F, Hurtado A, Ruschel J, Flynn K, Laskowski C, Umlauf M, et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science. 2011;331(6019):928-31.

Leehey D, Singh A, Bast J, Sethupathi P, Singh R. Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. Transl Res. 2008;151(4):208-16.

Michael S, Ganesh R, Viswanathan P. Effect of long acting insulin supplementation on diabetic nephropathy in Wistar rats. Indian J Exp Biol. 2012;50(12):867-74.

Yamashita Y, Egashira N, Masuguchi K, Ushio S, Kawashiri T, and Oishi R, “Comparison of peripheral neuropathy induced by standard and nanoparticle albumin-bound paclitaxel in rats,” J Pharmacol Sci. 2011;117(2):116-20.

Chen H, Brahmbhatt S, Gupta A and Sharma A. Duration of streptozotocin-induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK) phosphorylation in renal and vascular dysfunction. Cardiovascular Diabetology. 2005;4(1):3-11.

SuvarnaK, LaytonC, Bancroft J. Theory and Practice of Histological Techniques, 7th ed. Philadelphia, USA: Churchill Livingstone of Elsevier; 2013:173-214.

Kiernan J. Histological and Histochemical Methods: Theory and Practice. 4th ed. Bloxham UK, Scion; 2008:190-213.

Sulkowski S, Wincewicz A, Sulkowska M, Koda M. Transforming growth factor-beta1 and regulators of apoptosis. Ann N Y Acad Sci. 2009;1171:116-23.

Matsubara T, Abe H, Arai H, Nagai K, Mima A, Kanamori H, et al. Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab Invest. 2006;86(4):357-68.

Schoonjans F., Zalata A., Depuydt C. and Comhaire F. MedCalc: a new computer program for medical statistics. Computer Methods and programs in Biomedicine. 1995;48:257-62.

Goldberg R. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94(9):3171-82.

Galkina E and Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol. 2006;17(2):368-77.

Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2013;124(3):139-52.

Chang A, Hathaway C, Smithies O, Kakoki M. Transforming growth factor β1 and diabetic nephropathy. Am J Physiol Renal Physiol 2015:ajprenal.00502.2015.

Ina K, Kitamura H, Tatsukawa S, Takayama T, Fujikura Y, Shimada T. Transformation of interstitial fibroblasts and tubulointerstitial fibrosis in diabetic nephropathy. Med Electron Microsc 2002;35(2):87-95.

Qian Y, Feldman E, Pennathur S, Kretzler M, and Brosius F. “From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy,” Diabetes. 2008;57(6):1439-45.

Bonventre J. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol. 2012;32(5):452-62.

Katz A, Caramori M, Sisson-Ross S, Groppoli T, Basgen J, Mauer M. An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients. Kidney Int. 2002;61:2058-66.

Koesters R, Kaissling B, Lehir M, Picard N, Theilig F, Gebhardt R, et al. Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol. 2010;177(2):632-43.

Gradishar W, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-803.

Von Hoff D, Ramanathan R, Borad M, Laheru D, Smith L, Wood T, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29(34):4548-54.

Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas P, Megias D, Guerra C, et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer. 2013;109(4):926-33.

Sun L, Zhang D, Liu F, Xiang X, Ling G, Xiao L, et al. Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192. J Pathol. 2011;225(3):364-77.

Jordan M, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004;4(4):253-65.

Wang C, Song X, Li Y, Han F, Gao S, Wang X, et al. Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway via miR-140 upregulation. PLoS One. 2013;8(8):e70725.

Zhang D, Sun L, Xian W, Liu F, Ling G, Xiao L, et al. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-β/Smad activity. Lab Invest. 2010;90(3):436-47.

Karbalay-Doust S, Noorafshan A, Pourshahid S. Taxol and taurine protect the renal tissue of rats after unilateral ureteral obstruction: a stereological survey. Korean J Urol. 2012;53(5):360-7.