A sorafenib-induced model of glomerular kidney disease

A. Stavniichuk, O. Savchuk, Abdul Hye Khan, Wojciech K. Jankiewicz, John D. Smith
Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv; The Medical College of Wisconsin, Milwaukee, WI; The Medical College of Wisconsin, Milwaukee, WI; The Medical College of Wisconsin, Milwaukee, WI

Abstract


Glomerular damage and proteinuria are important pathophysiological signs of chronic kidney disease. This study provides data obtained using a model developed based on the use of the anti-cancer drug sorafenib. Sorafenib is a tyrosine kinase inhibitor that acts through the signaling pathway associated with vascular endothelial growth factor and is widely used to treat various types of cancer. Sorafenib, on the other hand, causes serious side effects in patients, including the development of chronic kidney disease. This study was aimed at using the nephrotoxic properties of sorafenib to model chronic kidney disease in rats. We showed that rats treated with sorafenib for 8 weeks along with a diet high in salt (8% NaCl) develop hypertension with high systolic blood pressure of 80 mmHg, proteinuria with an increase in protein content of 75% higher , and a 4-fold increase in glomerular damage compared to the control group. In case of damage to the renal glomeruli caused by sorafenib, the level of transcripts that are involved in the synthesis of key glomerular proteins such as nephrine, podocin, synaptopodin and subplanin is significantly reduced. Also, when studying this model, activation of the endothelial-mesenchymal transition is observed. In the group of rats treated with sorafenib, the mRNA level for the WT-1 endothelial cell marker was reduced by 20%, while the concentration of the Col III, FSP-1, α-SMA and vimentin mesenchymal cell markers increased by 2–3 times. Thus, we developed a preclinical model of chronic kidney disease, expressed in damage to the renal glomeruli. We also demonstrated that glomerular damage in this model is associated with decreased expression of key structural glomerular proteins and activation of the endothelial-mesenchymal transition of the kidneys.

Keywords


sorafenib, vascular endothelial growth factor, glomerular injury

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References


Asada N., Takase M., Nakamura J. et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J Clin Investig. 2011;121(10): 3981–90.

Bair S. M., Choueiri T. K., Moslehi J. Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med. 2013 May; 23(4): 104–13.

Boursiquot B. C., Zabor E. C., Glezerman I. G., Jaimes E. A. Hypertension and VEGF (Vascular Endothelial Growth Factor) Receptor Tyrosine Kinase Inhibition: Effects on Renal Function. Hypertension. 2017. Jul 24. pii: HYPERTENSIONAHA.117.09275.

Broxterman H. J., Georgopapadakou N. H. Anticancer therapeutics: "Addictive" targets, multitargeted drugs, new drug combinations. Drug Resist Updat. 2005 Aug; 8(4): 183–197.

Donoviel D. B., Freed D.D., Vogel H. et al. Proteinuria and perinatal lethality in mice lackingNEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol. 2001; 21(14): 4829–4836.

Eremina V., Quaggin S. E. Biology of anti-angiogenic therapyinduced thrombotic microangiopathy. Seminars in nephrology. 2010; 30(6): 582–590.

Eremina V., Sood M., Haigh J. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin Invest. 2003; 111(5): 707–716.

Eskens F. A., Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors a review. Eur J Cancer. 2006; 42(18): 3127–3139.

Garovic V. D., Wagner S. J., Petrovic L. M. et al. Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia. Nephrol Dial Transplant. 2007; 22(4): 1136–1143.

Gu J. W., Manning R. D. Jr., Young E. et al. Vascular endothelial growth factor receptor inhibitor enhances dietary salt induced hypertension in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol. 2009; 297(1): R142–R148.

Hamnvik O. P., Choueiri T. K., Turchin A. et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer. 2015 Jan 15; 121(2): 311–319.

Hayman S. R., Leung N., Grande J. P., Garovic V. D. VEGF inhibition, hypertension, and renal toxicity. Curr Oncol Rep. 2012 Aug; 14(4): 285–294.

Hye Khan M. A., Kolb L., Skibba M. et al. A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes. Diabetologia. 2018 Oct; 61(10): 2235–2246.

Jászai J., Schmidt M. H. H. Trends and Challenges in Tumor AntiAngiogenic Therapies. Cells. 2019; 8(9): 1102.

Kitamoto Y., Tokunaga H., Miyamoto K., Tomita K. VEGF is an essential molecule for glomerular structuring. Nephrol Dial Transplant. 2002; 17(Suppl 9): 25–27.

Lankhorst S., Baelde H. J., Clahsen-van Groningen M. C. et al. Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib. Nephrol Dial Transplant. 2016; 31(6): 914–921.

Liu F., Zhang S., Xu R. et al. Melatonin Attenuates Endothelial-toMesenchymal Transition of Glomerular Endothelial Cells via Regulating miR-497/ROCK in Diabetic Nephropathy. Kidney Blood Press Res. 2018; 43(5): 1425–1436.

Ma Z., Zhu L., Liu Y. et al. Lovastatin Alleviates Endothelial-toMesenchymal Transition in Glomeruli via Suppression of Oxidative Stress and TGF-β1 Signaling. Front Pharmacol. 2017 Jul 18; 8: 473.

Machnik A., Dahlmann A., Kopp C. et al. Mononuclear phagocytes system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces saltsensitive hypertension in rats. Hypertension. 2010; 55(3): 755–761.

Mantia C. M., McDermott D. F. Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma. Cancer. 2019; 125(23): 4148–4157.

Nagasawa T., Hye Khan M. A., Imig J. D. Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib. Clin Exp Pharmacol Physiol. 2012 May; 39(5): 454–461.

Ollero M., Sahali D. Inhibition of the VEGF signaling pathway and glomerular disorders. Nephrol Dial Transplant. 2015 Sep; 30(9): 1449–1455.

Piera-Velazquez S., Li Z., Jimenez S. A. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol. 2011; 179: 1074–1080.

Shankland S. J. The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006 Jun;69(12): 2131–2147.

Sugimoto H., Hamano Y., Charytan D., Cosgrove D., Kieran M., Sudhakar A., Kalluri R. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278(15): 12605–12608.

Van den Meiracker A. H., Danser A. H. Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition. Hypertension. 2016; 68(1): 17–23.

Wu S., Chen J. J., Kudelka A. et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008 Feb; 9(2): 117–123.

Zhao L., Zhao J., Wang X. et al. Serum response factor induces endothelial-mesenchymal transition in glomerular endothelial cells to aggravate proteinuria in diabetic nephropathy. Physiol Genomics. 2016 Oct 1; 48(10): 711–718.

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Received: 22.04.2020

Revised: 25.05.2020

Signed for press: 26.05.2020




DOI: http://dx.doi.org/10.17721/1728_2748.2020.81.25-31

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