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High FFA levels related to microalbuminuria and uncoupling of VEGF-NO axis in obese rats

  • Nephrology - Original Paper
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Abstract

Purpose

The objectives of this study were to test whether elevated free fatty acids (FFA) from visceral fat accumulation is related to increased urinary albumin excretion and whether fenofibrate has renal protective effects by regulating vascular endothelial growth factor-nitric oxide (VEGF-NO) axis in rats with diet-induced obesity.

Methods

Wistar rats were randomly divided into groups fed a normal diet, a high-fat diet, and a high-fat diet plus fenofibrate. Blood and urine samples were collected. Endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV) of the aorta. Renal tissues were collected for CD31 immunohistochemistry. Glomerular NO and VEGF expression were measured by Griess reaction and Western blot, respectively.

Results

At the end of 24 weeks, plasma FFA and triglyceride levels significantly increased in the obese rats. Fenofibrate intervention decreased serum FFA and triglyceride levels by 43.4 and 48 %, respectively, accompanied by a reduced visceral fat index. Urinary albumin/creatinine ratio increased in obese rats, which decreased 62.6 % after fenofibrate intervention. Severe EDV impairment was observed in obese rats; this was partially improved by fenofibrate. CD31 expression in glomeruli increased in obese rats, indicating increased endothelial cell proliferation. Obese rats showed increased glomerular VEGF expression and reduced NO levels. This uncoupling of VEGF-NO axis was partially improved by fenofibrate.

Conclusion

Elevated circulating FFA level may cause increased microalbuminuria in obese rats due to impairment of EDV; increased microalbuminuria can be improved by fenofibrate intervention. The mechanism may be related to FFA-induced uncoupling of VEGF-NO axis and endothelial dysfunction.

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References

  1. Dey A, Williams RS, Pollock DM, Stepp DW, Newman JW, Hammock BD et al (2004) Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria. Obes Res 12(8):1278–1289

    Article  PubMed  CAS  Google Scholar 

  2. Kawar B, Bello AK, El NAM (2009) High prevalence of microalbuminuria in the overweight and obese population: data from a UK population screening programme. Nephron Clin Pract 112(3):c205–c212

    Article  PubMed  CAS  Google Scholar 

  3. Klausen KP, Parving HH, Scharling H, Jensen JS (2009) Microalbuminuria and obesity: impact on cardiovascular disease and mortality. Clin Endocrinol (Oxf) 71(1):40–45

    Article  CAS  Google Scholar 

  4. Tebbe U, Bramlage P, Thoenes M, Paar WD, Danchin N, Volpe M et al (2009) Prevalence of microalbuminuria and its associated cardiovascular risk: German and Swiss results of the recent global i-SEARCH survey. Swiss Med Wkly 139(33–34):473–480

    PubMed  Google Scholar 

  5. Kalaitzidis RG, Siamopoulos KC (2011) The role of obesity in kidney disease: recent findings and potential mechanisms. Int Urol Nephrol 43(3):771–784

    Article  PubMed  Google Scholar 

  6. de Jong PE, Verhave JC, Pinto-Sietsma SJ, Hillege HL (2002) Obesity and target organ damage: the kidney. Int J Obes Relat Metab Disord 26(Suppl 4):S21–S24

    Article  PubMed  Google Scholar 

  7. Tamba S, Nakatsuji H, Kishida K, Noguchi M, Ogawa T, Okauchi Y et al (2010) Relationship between visceral fat accumulation and urinary albumin-creatinine ratio in middle-aged Japanese men. Atherosclerosis 211(2):601–605

    Article  PubMed  CAS  Google Scholar 

  8. Foster MC, Hwang SJ, Massaro JM, Hoffmann U, Deboer IH, Robins SJ et al (2011) Association of subcutaneous and visceral adiposity with albuminuria: the framingham heart study. Obesity (Silver Spring) 19(6):1284–1289

    Article  CAS  Google Scholar 

  9. Kume S, Uzu T, Araki S, Sugimoto T, Isshiki K, Chin-Kanasaki M et al (2007) Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol 18(10):2715–2723

    Article  PubMed  CAS  Google Scholar 

  10. Deji N, Kume S, Araki S, Soumura M, Sugimoto T, Isshiki K et al (2009) Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am J Physiol Renal Physiol 296(1):F118–F126

    Article  PubMed  CAS  Google Scholar 

  11. Stehouwer CD, Smulders YM (2006) Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol 17(8):2106–2111

    Article  PubMed  CAS  Google Scholar 

  12. Nakagawa T (2007) Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. Am J Physiol Renal Physiol 292(6):F1665–F1672

    Article  PubMed  CAS  Google Scholar 

  13. Nakagawa T, Sato W, Sautin YY, Glushakova O, Croker B, Atkinson MA et al (2006) Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy. J Am Soc Nephrol 17(3):736–745

    Article  PubMed  CAS  Google Scholar 

  14. Li H, Li H, Bao Y, Zhang X, Yu Y (2010) Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-kappaB pathway in rat aorta. Int J Cardiol 152(2):218–224

    Article  PubMed  Google Scholar 

  15. Srivastava RA, Jahagirdar R, Azhar S, Sharma S, Bisgaier CL (2006) Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. Mol Cell Biochem 285(1–2):35–50

    Article  PubMed  CAS  Google Scholar 

  16. Deng G, Long Y, Yu YR, Li MR (2010) Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK-eNOS Pathway. Int J Obes (Lond) 34(1):165–171

    Article  CAS  Google Scholar 

  17. Lane PH, Steffes MW, Mauer SM (1992) Estimation of glomerular volume: a comparison of four methods. Kidney Int 41(4):1085–1089

    Article  PubMed  CAS  Google Scholar 

  18. Kono T, Saito M, Kinoshita Y, Satoh I, Shinbori C, Satoh K (2006) Real-time monitoring of nitric oxide and blood flow during ischemia-reperfusion in the rat testis. Mol Cell Biochem 286(1–2):139–145

    Article  PubMed  CAS  Google Scholar 

  19. Asaba K, Tojo A, Onozato ML, Goto A, Quinn MT, Fujita T et al (2005) Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 67(5):1890–1898

    Article  PubMed  CAS  Google Scholar 

  20. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD (2001) Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 59(4):1498–1509

    Article  PubMed  CAS  Google Scholar 

  21. Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall JE (2001) Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 12(6):1211–1217

    PubMed  CAS  Google Scholar 

  22. Pinto-Sietsma SJ, Navis G, Janssen WM, de Zeeuw D, Gans RO, de Jong PE (2003) A central body fat distribution is related to renal function impairment, even in lean subjects. Am J Kidney Dis 41(4):733–741

    Article  PubMed  Google Scholar 

  23. Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH (2002) Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 51(4):1157–1165

    Article  PubMed  CAS  Google Scholar 

  24. Deen WM (2004) What determines glomerular capillary permeability. J Clin Invest 114(10):1412–1414

    PubMed  CAS  Google Scholar 

  25. Feliers D, Chen X, Akis N, Choudhury GG, Madaio M, Kasinath BS (2005) VEGF regulation of endothelial nitric oxide synthase in glomerular endothelial cells. Kidney Int 68(4):1648–1659

    Article  PubMed  CAS  Google Scholar 

  26. Satoh M, Fujimoto S, Arakawa S, Yada T, Namikoshi T, Haruna Y et al (2008) Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy. Nephrol Dial Transplant 23(12):3806–3813

    Article  PubMed  CAS  Google Scholar 

  27. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR et al (2011) Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54(2):280–290

    Article  PubMed  CAS  Google Scholar 

  28. Tanaka Y, Kume S, Araki S, Isshiki K, Chin-Kanasaki M, Sakaguchi M et al (2011) Fenofibrate, a PPARalpha agonist, has renoprotective effects in mice by enhancing renal lipolysis. Kidney Int 79(8):871–882

    Article  PubMed  CAS  Google Scholar 

  29. Goetze S, Eilers F, Bungenstock A, Kintscher U, Stawowy P, Blaschke F et al (2002) PPAR activators inhibit endothelial cell migration by targeting Akt. Biochem Biophys Res Commun 293(5):1431–1437

    Article  PubMed  CAS  Google Scholar 

  30. Olukman M, Sezer ED, Ulker S, Sozmen EY, Cinar GM (2010) Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats. Exp Diabetes Res 2010:828531

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Natural Science Foundation of China (Grants no. 81070675).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, No. 37, Guoxue Road, Chengdu, 610041, Sichuan, China

    Xiaodong Sun, Yerong Yu & Lina Han

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  1. Xiaodong Sun
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  2. Yerong Yu
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  3. Lina Han
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Correspondence to Yerong Yu.

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Sun, X., Yu, Y. & Han, L. High FFA levels related to microalbuminuria and uncoupling of VEGF-NO axis in obese rats. Int Urol Nephrol 45, 1197–1207 (2013). https://doi.org/10.1007/s11255-013-0428-9

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  • DOI: https://doi.org/10.1007/s11255-013-0428-9

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