NAD+ Protects against Hyperlipidemia-induced Kidney Injury in Apolipoprotein E-deficient Mice


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Abstract

Background:Hyperlipidemia is an independent risk factor for kidney injury. Several studies have shown that nicotinamide adenine dinucleotide (NAD+) is an important coenzyme involved in normal body metabolism. Therefore, this study aimed to investigate the possible protective effects of NAD+ against hyperlipidemia-induced kidney injury in apolipoprotein E-deficient (ApoE-/-) mice.

Methods:Twenty-five eight-week-old male ApoE-/- mice were randomly assigned into four groups: normal diet (ND), ND supplemented with NAD+ (ND+NAD+), high-fat diet (HFD), and HFD supplemented with NAD+ (HFD+NAD+). The mice were subjected to their respective diets for a duration of 16 weeks. Blood samples were obtained from the inferior vena cava, collected in serum tubes, and stored at -80 °C until use. Kidney tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the kidney tissues was snap-frozen in liquid nitrogen for Western blot analysis.

Results:Metabolic parameters (total cholesterol, triglycerides, low-density lipoprotein-cholesterol, creatinine, and blood urea nitrogen) were significantly higher in the HFD group compared to the other groups. Histological analysis revealed prominent pathological manifestations in the kidneys of the HFD group. The HFD+NAD+ group showed increased levels of oxidative stress markers (NRF2 and SOD2) and decreased levels of NOX4 compared to the HFD group. Furthermore, the HFD group exhibited higher levels of TGF-β, Smad3, Collagen I, Collagen III, Bax, and Bak compared to the other groups. NAD+ supplementation in the HFD+NAD+ group significantly increased the levels of SIRT3, HO-1, Bcl-2, and Bcl-xL compared to the HFD group. Additionally, NF-κB protein expression was higher in the HFD group than in the HFD+NAD+ group.

Conclusion:These findings demonstrated that NAD+ may hold potential as a clinical treatment for kidney injury caused by hyperlipidemia.

About the authors

Zuowei Pei

Department of Cardiology, Central Hospital of Dalian University of Technology

Author for correspondence.
Email: info@benthamscience.net

Yu Li

Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University

Email: info@benthamscience.net

Wei Yao

Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University

Email: info@benthamscience.net

Feiyi Sun

Health Medical Department, Central Hospital of Dalian University of Technology

Email: info@benthamscience.net

Xiaofang Pan

Health Medical Department, Central Hospital of Dalian University of Technology

Author for correspondence.
Email: info@benthamscience.net

References

  1. Song, Y.; Liu, J.; Zhao, K.; Gao, L.; Zhao, J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metab., 2021, 33(10), 1911-1925. doi: 10.1016/j.cmet.2021.09.001 PMID: 34562355
  2. Ding, M.; Si, D.; Zhang, W.; Feng, Z.; He, M.; Yang, P. Red yeast rice repairs kidney damage and reduces inflammatory transcription factors in rat models of hyperlipidemia. Exp. Ther. Med., 2014, 8(6), 1737-1744. doi: 10.3892/etm.2014.2035 PMID: 25371725
  3. Ruan, X.Z.; Varghese, Z.; Moorhead, J.F. An update on the lipid nephrotoxicity hypothesis. Nat. Rev. Nephrol., 2009, 5(12), 713-721. doi: 10.1038/nrneph.2009.184 PMID: 19859071
  4. Tokgözoğlu, L.; Casula, M.; Pirillo, A.; Catapano, A.L. Similarities and differences between European and American guidelines on the management of blood lipids to reduce cardiovascular risk. Atheroscler. Suppl., 2020, 42, e1-e5. doi: 10.1016/j.atherosclerosissup.2021.01.001 PMID: 33589218
  5. Chirumamilla, R.; Mina, D.; Siyahian, S.; Park, M. Subclinical metabolic and cardiovascular abnormalities in autosomal dominant polycystic kidney disease. Clin. Nephrol., 2018, 90(4), 237-245. doi: 10.5414/CN109233 PMID: 30106364
  6. Tanaka, A.; Nakamura, T.; Sato, E.; Chihara, A.; Node, K. Effect of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator (SPPARMα), on urinary protein excretion in IgA nephropathy with hypertriglyceridemia. CEN Case Rep., 2020, 9(2), 141-146. doi: 10.1007/s13730-020-00444-2 PMID: 31950425
  7. Gong, P.; Zhang, Z.; Zhang, D.; Zou, Z.; Zhang, Q.; Ma, H.; Li, J.; Liao, L.; Dong, J. Effects of endothelial progenitor cells transplantation on hyperlipidemia associated kidney damage in ApoE knockout mouse model. Lipids Health Dis., 2020, 19(1), 53. doi: 10.1186/s12944-020-01239-1 PMID: 32209093
  8. Kuwahara, M.; Bannai, K.; Segawa, H.; Miyamoto, K.; Yamato, H. Cardiac remodeling associated with protein increase and lipid accumulation in early-stage chronic kidney disease in rats. Biochim. Biophys. Acta Mol. Basis Dis., 2014, 1842(9), 1433-1443. doi: 10.1016/j.bbadis.2014.04.026 PMID: 24798235
  9. Ralto, K.M.; Rhee, E.P.; Parikh, S.M. NAD+ homeostasis in renal health and disease. Nat. Rev. Nephrol., 2020, 16(2), 99-111. doi: 10.1038/s41581-019-0216-6 PMID: 31673160
  10. Hershberger, K.A.; Martin, A.S.; Hirschey, M.D. Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat. Rev. Nephrol., 2017, 13(4), 213-225. doi: 10.1038/nrneph.2017.5 PMID: 28163307
  11. Hossain, E.; Li, Y.; Anand-Srivastava, M.B. Angiotensin II-induced overexpression of sirtuin 1 contributes to enhanced expression of Giα proteins and hyperproliferation of vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol., 2021, 321(3), H496-H508. doi: 10.1152/ajpheart.00898.2020 PMID: 34270373
  12. Covarrubias, A.J.; Perrone, R.; Grozio, A.; Verdin, E. NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol., 2021, 22(2), 119-141. doi: 10.1038/s41580-020-00313-x PMID: 33353981
  13. Chini, C.C.S.; Zeidler, J.D.; Kashyap, S.; Warner, G.; Chini, E.N. Evolving concepts in NAD+ metabolism. Cell Metab., 2021, 33(6), 1076-1087. doi: 10.1016/j.cmet.2021.04.003 PMID: 33930322
  14. Tannous, C.; Booz, G.W.; Altara, R.; Muhieddine, D.H.; Mericskay, M.; Refaat, M.M.; Zouein, F.A. Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases. Acta Physiol. (Oxf.), 2021, 231(3)e13551 doi: 10.1111/apha.13551 PMID: 32853469
  15. Bugarski, M.; Ghazi, S.; Polesel, M.; Martins, J.R.; Hall, A.M. Changes in NAD and lipid metabolism drive acidosis-induced acute kidney injury. J. Am. Soc. Nephrol., 2021, 32(2), 342-356. doi: 10.1681/ASN.2020071003 PMID: 33478973
  16. Pazoki-Toroudi, H.R.; Hesami, A.; Vahidi, S.; Sahebjam, F.; Seifi, B.; Djahanguiri, B. The preventive effect of captopril or enalapril on reperfusion injury of the kidney of rats is independent of angiotensin II AT1 receptors. Fundam. Clin. Pharmacol., 2003, 17(5), 595-598. doi: 10.1046/j.1472-8206.2003.00188.x PMID: 14703720
  17. Wahba, I.M.; Mak, R.H. Obesity and obesity-initiated metabolic syndrome: Mechanistic links to chronic kidney disease. Clin. J. Am. Soc. Nephrol., 2007, 2(3), 550-562. doi: 10.2215/CJN.04071206 PMID: 17699463
  18. Arany, I.; Hall, S.; Reed, D.K.; Reed, C.T.; Dixit, M. Nicotine enhances high-fat diet-induced oxidative stress in the kidney. Nicotine Tob. Res., 2016, 18(7), 1628-1634. doi: 10.1093/ntr/ntw029 PMID: 26896163
  19. Soetikno, V.; Sari, S.; Ul Maknun, L.; Sumbung, N.; Rahmi, D.; Pandhita, B.; Louisa, M.; Estuningtyas, A. Pre-treatment with curcumin ameliorates cisplatin-induced kidney damage by suppressing kidney inflammation and apoptosis in rats. Drug Res. (Stuttg.), 2019, 69(2), 75-82. doi: 10.1055/a-0641-5148 PMID: 29945277
  20. Kang, B.E.; Choi, J.Y.; Stein, S.; Ryu, D. Implications of NAD + boosters in translational medicine. Eur. J. Clin. Invest., 2020, 50(10)e13334 doi: 10.1111/eci.13334 PMID: 32594513
  21. Gai, Z.; Wang, T.; Visentin, M.; Kullak-Ublick, G.; Fu, X.; Wang, Z. Lipid accumulation and chronic kidney disease. Nutrients, 2019, 11(4), 722. doi: 10.3390/nu11040722 PMID: 30925738
  22. Qian, C.; Yang, Q.; Guo, L.; Zhu, H.; You, X.; Liu, H.; Sun, Y. Exercise reduces hyperlipidemia induced kidney damage in apolipoprotein E deficient mice. Exp. Ther. Med., 2020, 21(2), 153. doi: 10.3892/etm.2020.9585 PMID: 33456520
  23. Scheuer, H.; Gwinner, W.; Hohbach, J.; Gröne, E.F.; Brandes, R.P.; Malle, E.; Olbricht, C.J.; Walli, A.K.; Gröne, H.J. Oxidant stress in hyperlipidemia-induced renal damage. Am. J. Physiol. Renal Physiol., 2000, 278(1), F63-F74. doi: 10.1152/ajprenal.2000.278.1.F63 PMID: 10644656
  24. Napoli, C.; Lerman, L.O. Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia. Mayo Clin. Proc., 2001, 76(6), 619-631. doi: 10.1016/S0025-6196(11)62413-0 PMID: 11393501
  25. Aminzadeh, M.A.; Nicholas, S.B.; Norris, K.C.; Vaziri, N.D. Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy. Nephrol. Dial. Transplant., 2013, 28(8), 2038-2045. doi: 10.1093/ndt/gft022 PMID: 23512109
  26. Calkins, M.J.; Johnson, D.A.; Townsend, J.A.; Vargas, M.R.; Dowell, J.A.; Williamson, T.P.; Kraft, A.D.; Lee, J.M.; Li, J.; Johnson, J.A. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox Signal., 2009, 11(3), 497-508. doi: 10.1089/ars.2008.2242 PMID: 18717629
  27. Annaldas, S.; Saifi, M.A.; Khurana, A.; Godugu, C. Nimbolide ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibition of TGF-β and EMT/Slug signalling. Mol. Immunol., 2019, 112, 247-255. doi: 10.1016/j.molimm.2019.06.003 PMID: 31202101
  28. Il Jeong, S.; Ju Kim, K.; Kug Choo, Y.; Soo Keum, K.; Kyu Choi, B.; Yong Jung, K. Phytolacca americana inhibits the high glucose-induced mesangial proliferation via suppressing extracellular matrix accumulation and TGF-β production. Phytomedicine, 2004, 11(2-3), 175-181. doi: 10.1078/0944-7113-00291 PMID: 15070169
  29. Meng, X.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-β The master regulator of fibrosis. Nat. Rev. Nephrol., 2016, 12(6), 325-338. doi: 10.1038/nrneph.2016.48 PMID: 27108839
  30. Youle, R.J.; Strasser, A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol., 2008, 9(1), 47-59. doi: 10.1038/nrm2308 PMID: 18097445
  31. Domino, M.; Jasinski, T.; Kautz, E.; Juszczuk-Kubiak, E.; Ferreira-Dias, G.; Zabielski, R.; Sady, M.; Gajewski, Z. Expression of genes involved in the NF-κB-dependent pathway of the fibrosis in the mare endometrium. Theriogenology, 2020, 147, 18-24. doi: 10.1016/j.theriogenology.2020.01.055 PMID: 32074495
  32. Umezawa, K. Possible role of peritoneal NF-κB in peripheral inflammation and cancer: Lessons from the inhibitor DHMEQ. Biomed. Pharmacother., 2011, 65(4), 252-259. doi: 10.1016/j.biopha.2011.02.003 PMID: 21723080
  33. Sosińska, P.; Baum, E.; Maćkowiak, B.; Staniszewski, R.; Jasinski, T.; Umezawa, K.; Bręborowicz, A. Inhibition of NF-kappaB with Dehydroxymethylepoxyquinomicin modifies the function of human peritoneal mesothelial cells. Am. J. Transl. Res., 2016, 8(12), 5756-5765. PMID: 28078047
  34. Zhang, Z.Y.; Wang, N.; Qian, L.L.; Dang, S.P.; Wu, Y.; Tang, X.; Liu, X.Y.; Wang, R.X. Zhonghua Xin Xue Guan Bing Za Zhi, 2020, 48(5), 401-407. Impact and related mechanisms of glucose fluctuations on aortic fibrosis in type 1 diabetic rats PMID: 32450657

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