Abstract
Aim:
Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.
Methods:
Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg−1·d−1, ip), or BSA plus enalapril (0.5 g·kg−1·d−1, po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.
Results:
BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68+ cells (macrophages) and CD3+ cells (T lymphocytes), particularly of CD20+ cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.
Conclusion:
Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
D'Amico G, Bazzi C . Pathophysiology of proteinuria. Kidney Int 2003; 63: 809–25.
Zoja C, Morigi M, Remuzzi G . Proteinuria and phenotypic change of proximal tubular cells. J Am Soc Nephrol 2003; 14 Suppl 1: S36–41.
Zandi-Nejad K, Eddy AA, Glassock RJ, Brenner BM . Why is proteinuria an ominous biomarker of progressive kidney disease? Kidney Int Suppl 2004; (92): S76–89.
How HY, Sibai BM . Use of angiotensin-converting enzyme inhibitors in patients with diabetic nephropathy. J Matern Fetal Neonatal Med 2002; 12: 402–7.
Baltatzi M, Savopoulos C, Hatzitolios A . Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results. Hippokratia 2011; 15: 27–32.
Radaelli A, Loardi C, Cazzaniga M, Balestri G, DeCarlini C, Cerrito MG, et al. Inflammatory activation during coronary artery surgery and its dose-dependent modulation by statin/ACE-inhibitor combination. Arterioscler Thromb Vasc Biol 2007; 27: 2750–5.
Fu R, Chen Z, Wang Q, Guo Q, Xu J, Wu X . XJP-1, a novel ACEI, with anti-inflammatory properties in HUVECs. Atherosclerosis 2011; 219: 40–8.
Ogura Y, Sutterwala FS, Flavell RA . The inflammasome: first line of the immune response to cell stress. Cell 2006; 126: 659–62.
Petrilli V, Papin S, Tschopp J . The inflammasome. Curr Biol 2005; 15: R581.
Tan MS, Yu JT, Jiang T, Zhu XC, Tan L . The NLRP3 Inflammasome in Alzheimer's disease. Mol Neurobiol 2013; 48: 875–82.
Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis. Hepatology 2014; 59: 898–910.
Martinon F, Agostini L, Meylan E, Tschopp J . Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 2004; 14: 1929–34.
Schroder K, Zhou R, Tschopp J . The NLRP3 inflammasome: a sensor for metabolic danger? Science 2010; 327: 296–300.
Anders HJ, Muruve DA . The inflammasomes in kidney disease. J Am Soc Nephrol 2011; 22: 1007–18.
Vilaysane A, Chun J, Seamone ME, Wang W, Chin R, Hirota S, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol 2010; 21: 1732–44.
Mulay SR, Kulkarni OP, Rupanagudi KV, Migliorini A, Darisipudi MN, Vilaysane A, et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J Clin Invest 2013; 123: 236–46.
Correa-Costa M, Braga TT, Semedo P, Hayashida CY, Bechara LR, Elias RM, et al. Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PLoS One 2011; 6: e29004.
Liu BC, Gao J, Li Q, Xu LM . Albumin caused the increasing production of angiotensin II due to the dysregulation of ACE/ACE2 expression in HK2 cells. Clin Chim Acta 2009; 403: 23–30.
Ding LH, Liu D, Xu M, Liu BC . Expression of NLRP3 inflammasome in the BSA-overloaded rats kidney. Chin J Nephrol 2014; 30: In press.
Pan MM, Zhang MH, Ni HF, Chen JF, Xu M, Phillips AO, et al. Inhibition of TGF-beta1/Smad signal pathway is involved in the effect of Cordyceps sinensis against renal fibrosis in 5/6 nephrectomy rats. Food Chem Toxicol 2013; 58: 487–94.
Dai HY, Zheng M, Tang RN, Ma KL, Ni J, Liu BC . Inhibition of integrin-linked kinase by angiotensin II receptor antagonist, irbesartan attenuates podocyte injury in diabetic rats. Chin Med J (Engl) 2012; 125: 888–93.
Chen JF, Ni HF, Pan MM, Liu H, Xu M, Zhang MH, et al. Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats. Am J Physiol Renal Physiol 2013; 304: F676–85.
Baines RJ, Brunskill NJ . Tubular toxicity of proteinuria. Nat Rev Nephrol 2011; 7: 177–80.
Kruger D . The pathophysiology, diagnosis, and management of proteinuria. JAAPA 2012; 25: 32–7.
Wu CC, Chen JS, Lu KC, Chen CC, Lin SH, Chu P, et al. Aberrant cytokines/chemokines production correlate with proteinuria in patients with overt diabetic nephropathy. Clin Chim Acta 2010; 411: 700–4.
Cao Z, Cooper ME . Role of angiotensin II in tubulointerstitial injury. Semin Nephrol 2001; 21: 554–62.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 2009; 183: 787–91.
Haneklaus M, O'Neill LA, Coll RC . Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol 2013; 25: 40–5.
Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J . Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 2008; 320: 674–7.
Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 2008; 452: 103–7.
Latz E, Xiao TS, Stutz A . Activation and regulation of the inflammasomes. Nat Rev Immunol 2013; 13: 397–411.
Fang L, Xie D, Wu X, Cao H, Su W, Yang J . Involvement of endoplasmic reticulum stress in albuminuria induced inflammasome activation in renal proximal tubular cells. PLoS One 2013; 8: e72344.
Acknowledgements
This study was supported by grants from the Key Project of the National Natural Science Foundation (No 81130010), National Key Basic Research Project (“973”) (No 2012CB517700), and Natural Science Foundation of Jiangsu Province (No BK201106; all to Bi-cheng LIU, Principle Investigator).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ding, Lh., Liu, D., Xu, M. et al. Enalapril inhibits tubulointerstitial inflammation and NLRP3 inflammasome expression in BSA-overload nephropathy of rats. Acta Pharmacol Sin 35, 1293–1301 (2014). https://doi.org/10.1038/aps.2014.66
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2014.66
Keywords
This article is cited by
-
Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1
Acta Pharmacologica Sinica (2019)
-
Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice
Scientific Reports (2017)
-
Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro
Acta Pharmacologica Sinica (2015)
-
FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway
Acta Pharmacologica Sinica (2014)
