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Blocking angiotensin 2 receptor attenuates diabetic nephropathy via mitigating ANGPTL2/TL4/NF-κB expression

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Abstract

Background

Diabetic nephropathy (DN) is a consequence of diabetes mellitus (DM) and is associated with early changes in renal angiotensin II (ANG II). These changes were evaluated using ANG II blocker valsartan early from week two of diabetes (experiment I, renoprotective) and late from week nine of diabetes (experiment II, renotherapeutic) to the end of both experiments at week twelve.

Methods and results

In both experiments, adult male Wister rats were divided into (i) vehicle group; (ii) valsartan received oral 30 mg/Kg/day; (iii) diabetic received single 50 mg/Kg intraperitoneal streptozotocin injection; (iv) renoprotection, diabetic rats received valsartan treated in experiments I and II. DM effects on urine albumin excretion, blood pressure, and renal ANG II were measured. Urinary nephrin, kidney injury molecule-1 (KIM-1), renal angiopoietin-like protein 2 (ANGPTL2), and toll-like receptor 4 (TLR 4) mRNA expression were tested. DM-initiated fibrotic markers integrin, α-smooth muscle actin expression, and collagen IV and apoptotic protein caspase 3 were tested. DM induced early changes starting from week four in the tested variables. At week twelve, in both experiments, valsartan intervention showed a significant reduction in ANG II, ANGPTL2, TLR 4 and integrin expression and improvement in albuminuria, blood pressure, urinary biomarkers, fibrotic and apoptotic markers.

Conclusions

Changes leading to DN starts early in the disease course and ANG II reduction decreased the expression of ANGPTL2 and integrin which preserve the glomerular barrier. Blocking ANG II was able to decrease TLR 4 and inflammatory cytokines leading to decreasing DN.

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References

  1. Palatini P (2012) Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension. Nephrol Dial Transplant 27:1708–1714. https://doi.org/10.1093/ndt/gfs037

    Article  PubMed  Google Scholar 

  2. Lin YC, Chang YH, Yang SY, Wu KD, Chu TS (2018) Update of pathophysiology and management of diabetic kidney disease. J Formos Med Assoc 117:662–675. https://doi.org/10.1016/j.jfma.2018.02.007

    Article  CAS  PubMed  Google Scholar 

  3. Cao Z, Cooper ME (2011) Pathogenesis of diabetic nephropathy. J Diabetes Investig 2:243–247. https://doi.org/10.1111/j.2040-1124.2011.00131.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Patinha D, Fasching A, Pinho D, Albino-Teixeira A, Morato M, Palm F (2013) Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors. Am J Physiol Renal Physiol 304:F614–F622. https://doi.org/10.1152/ajprenal.00285.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tuttle KR (2017) Back to the future: glomerular hyperfiltration and the diabetic kidney. Diabetes 66:14–16. https://doi.org/10.2337/dbi16-0056

    Article  CAS  PubMed  Google Scholar 

  6. Park S, Bivona BJ, Feng Y, Lazartigues E, Harrison-Bernard LM (2008) Intact renal afferent arteriolar autoregulatory responsiveness in db/db mice. Am J Physiol Renal Physiol 295:F1504–F1511. https://doi.org/10.1152/ajprenal.90417.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kandasamy Y, Smith R, Lumbers ER, Rudd D (2014) Nephrin—a biomarker of early glomerular injury. Biomark Res 2:21. https://doi.org/10.1186/2050-7771-2-21

    Article  PubMed  PubMed Central  Google Scholar 

  8. Akankwasa G, Jianhua L, Guixue C, Changjuan A, Xiaosong Q (2018) Urine markers of podocyte dysfunction: a review of podocalyxin and nephrin in selected glomerular diseases. Biomark Med 12:927–935. https://doi.org/10.2217/bmm-2018-0152

    Article  CAS  PubMed  Google Scholar 

  9. Peterson RG, Jackson CV, Zimmerman KM (2017) The ZDSD rat: a novel model of diabetic nephropathy. Am J Transl Res 9:4236–4249

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Suryavanshi SV, Kulkarni YA (2017) NF-kappabeta: a potential target in the management of vascular complications of diabetes. Front Pharmacol 8:798. https://doi.org/10.3389/fphar.2017.00798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Makary S, Abdo M, Hassan WA, Tawfik MK (2019) Angiotensin blockade attenuates diabetic nephropathy in hypogonadal adult male rats. Can J Physiol Pharmacol 97:708–720. https://doi.org/10.1139/cjpp-2018-0572

    Article  CAS  PubMed  Google Scholar 

  12. Lv J, Jia R, Yang D, Zhu J, Ding G (2009) Candesartan attenuates angiotensin II-induced mesangial cell apoptosis via TLR4/MyD88 pathway. Biochem Biophys Res Commun 380:81–86. https://doi.org/10.1016/j.bbrc.2009.01.035

    Article  CAS  PubMed  Google Scholar 

  13. Lin M, Yiu WH, Wu HJ, Chan LY, Leung JC, Au WS, Chan KW, Lai KN, Tang SC (2012) Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol 23:86–102. https://doi.org/10.1681/ASN.2010111210

    Article  CAS  PubMed  Google Scholar 

  14. Sanajou D, Ghorbani Haghjo A, Argani H, Roshangar L, Ahmad SNS, Jigheh ZA, Aslani S, Panah F, Rashedi J, Mesgari Abbasi M (2018) FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats. J Physiol Biochem 74:467–478. https://doi.org/10.1007/s13105-018-0640-2

    Article  CAS  PubMed  Google Scholar 

  15. Wen J, Ma Z, Livingston MJ, Zhang W, Yuan Y, Guo C, Liu Y, Fu P, Dong Z (2020) Decreased secretion and profibrotic activity of tubular exosomes in diabetic kidney disease. Am J Physiol Renal Physiol. https://doi.org/10.1152/ajprenal.00292.2020

    Article  PubMed  Google Scholar 

  16. Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM (1986) Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77:1925–1930. https://doi.org/10.1172/JCI112521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Anderson S, Rennke HG, Garcia DL, Brenner BM (1989) Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int 36:526–536

    Article  CAS  Google Scholar 

  18. Rizkalla B, Forbes JM, Cao Z, Boner G, Cooper ME (2005) Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes: role of the renin-angiotensin system. J Hypertens 23:153–164

    Article  CAS  Google Scholar 

  19. Gnudi L (2016) Angiopoietins and diabetic nephropathy. Diabetologia 59:1616–1620. https://doi.org/10.1007/s00125-016-3995-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang H, Ni H, Ma K, Zou J (2019) ANGPTL2 regulates autophagy through the MEK/ERK/Nrf-1 pathway and affects the progression of renal fibrosis in diabetic nephropathy. Am J Transl Res 11:5472–5486

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang S, Zhang J, Wang S, Shi J, Zhao X (2017) Knockdown of angiopoietin-like protein 2 ameliorates diabetic nephropathy by inhibiting TLR4. Cell Physiol Biochem 43:685–696. https://doi.org/10.1159/000480654

    Article  CAS  PubMed  Google Scholar 

  22. El-Asrar MA, Elbarbary NS, Ismail EA, Bakr AA (2016) Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness. Angiogenesis 19:421–431. https://doi.org/10.1007/s10456-016-9517-6

    Article  CAS  PubMed  Google Scholar 

  23. Trietley GS, Wilson SA, Chaudhri P, Payette N, Higbea A, Nashelsky J (2017) Clinical Inquiry: do ACE inhibitors or ARBs help prevent kidney disease in patients with diabetes and normal BP? J Fam Pract 66:257–263

    PubMed  Google Scholar 

  24. Currie G, Bethel MA, Holzhauer B, Haffner SM, Holman RR, McMurray JJV (2017) Effect of valsartan on kidney outcomes in people with impaired glucose tolerance. Diabetes Obes Metab 19:791–799. https://doi.org/10.1111/dom.12877

    Article  CAS  PubMed  Google Scholar 

  25. Katayama S, Yagi S, Yamamoto H, Yamaguchi M, Izumida T, Noguchi Y, Inaba M, Inukai K (2007) Is renoprotection by angiotensin receptor blocker dependent on blood pressure: the saitama medical school, albuminuria reduction in diabetics with valsartan (STAR) study. Hypertens Res 30:529–533. https://doi.org/10.1291/hypres.30.529

    Article  CAS  PubMed  Google Scholar 

  26. Tawfik MK (2012) Renoprotective activity of telmisartan versus pioglitazone on ischemia/reperfusion induced renal damage in diabetic rats. Eur Rev Med Pharmacol Sci 16:600–609

    PubMed  Google Scholar 

  27. Tesch GH, Allen TJ (2007) Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology (Carlton) 12:261–266. https://doi.org/10.1111/j.1440-1797.2007.00796.x

    Article  Google Scholar 

  28. Zhou SJ, Bai L, Lv L, Chen R, Li CJ, Liu XY, Yu DM, Yu P (2014) Liraglutide ameliorates renal injury in streptozotocininduced diabetic rats by activating endothelial nitric oxide synthase activity via the downregulation of the nuclear factorkappaB pathway. Mol Med Rep 10:2587–2594. https://doi.org/10.3892/mmr.2014.2555

    Article  CAS  PubMed  Google Scholar 

  29. Masoad RE, Ewais MM, Tawfik MK, Abd El-All HS (2012) Effect of mononuclear cells versus pioglitazone on streptozotocin-induced diabetic nephropathy in rats. Pharmacol Rep 64:1223–1233

    Article  CAS  Google Scholar 

  30. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE (2005) Recommendations for blood pressure measurement in humans and experimental animals: part 2: blood pressure measurement in experimental animals: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Arterioscler Thromb Vasc Biol 25:e22-33. https://doi.org/10.1161/01.ATV.0000158419.98675.d7

    Article  CAS  PubMed  Google Scholar 

  31. Makary S, Abdo M, Fekry E (2017) Oxidative stress burden inhibits spermatogenesis in adult male rats: testosterone protective effect. Can J Physiol Pharmacol 96:457

    Google Scholar 

  32. Sun H, Zheng JM, Chen S, Zeng CH, Liu ZH, Li LS (2007) Enhanced expression of ANGPTL2 in the microvascular lesions of diabetic glomerulopathy. Nephron Exp Nephrol 105:e117–e123. https://doi.org/10.1159/000100493

    Article  CAS  PubMed  Google Scholar 

  33. Elshaer RE, Tawfik MK, Nosseir N, El-Ghaiesh SH, Toraih EA, Elsherbiny NM, Zaitone SA (2019) Leflunomide-induced liver injury in mice: Involvement of TLR4 mediated activation of PI3K/mTOR/NFkappaB pathway. Life Sci 235:116824. https://doi.org/10.1016/j.lfs.2019.116824

    Article  CAS  PubMed  Google Scholar 

  34. Tawfik MK, El-Kherbetawy MK, Makary S (2018) Cardioprotective and anti-aggregatory effects of levosimendan on isoproterenol-induced myocardial injury in high-fat-fed rats involves modulation of PI3K/Akt/mTOR signaling pathway and inhibition of apoptosis: comparison to cilostazol. J Cardiovasc Pharmacol Ther 23:456–471. https://doi.org/10.1177/1074248418763957

    Article  CAS  PubMed  Google Scholar 

  35. Elbe H, Vardi N, Esrefoglu M, Ates B, Yologlu S, Taskapan C (2015) Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum Exp Toxicol 34:100–113. https://doi.org/10.1177/0960327114531995

    Article  CAS  PubMed  Google Scholar 

  36. Nishi H (2016) Angiopoietin-like protein 2 and kidney fibrosis: lessons from knockout mice. Kidney Int 89:272–274. https://doi.org/10.1016/j.kint.2015.12.022

    Article  CAS  PubMed  Google Scholar 

  37. Morinaga J, Kadomatsu T, Miyata K, Endo M, Terada K, Tian Z, Sugizaki T, Tanigawa H, Zhao J, Zhu S, Sato M, Araki K, Iyama K, Tomita K, Mukoyama M, Tomita K, Kitamura K, Oike Y (2016) Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-beta signaling in chronic kidney disease. Kidney Int 89:327–341. https://doi.org/10.1016/j.kint.2015.12.021

    Article  CAS  PubMed  Google Scholar 

  38. Pozzi A, Zent R (2013) Integrins in kidney disease. J Am Soc Nephrol 24:1034–1039. https://doi.org/10.1681/ASN.2013010012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Niu H, Nie L, Liu M, Chi Y, Zhang T, Li Y (2014) Benazepril affects integrin-linked kinase and smooth muscle alpha-actin expression in diabetic rat glomerulus and cultured mesangial cells. BMC Nephrol 15:135. https://doi.org/10.1186/1471-2369-15-135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mohamed HE, Asker ME, Keshawy MM, Hasan RA, Mahmoud YK (2020) Inhibition of tumor necrosis factor-alpha enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance. Mol Cell Biochem. https://doi.org/10.1007/s11010-020-03686-x

    Article  PubMed  Google Scholar 

  41. Carmines PK (2010) The renal vascular response to diabetes. Curr Opin Nephrol Hypertens 19:85–90. https://doi.org/10.1097/MNH.0b013e32833240fc

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gilbert RE, Zhang Y, Williams SJ, Zammit SC, Stapleton DI, Cox AJ, Krum H, Langham R, Kelly DJ (2012) A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7:e47160. https://doi.org/10.1371/journal.pone.0047160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bunag RD, Tomita T, Sasaki S (1982) Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness. Hypertension 4:556–565

    Article  CAS  Google Scholar 

  44. Brooks DP, Nutting DF, Crofton JT, Share L (1989) Vasopressin in rats with genetic and streptozocin-induced diabetes. Diabetes 38:54–57. https://doi.org/10.2337/diab.38.1.54

    Article  CAS  PubMed  Google Scholar 

  45. Gagliardini E, Perico N, Rizzo P, Buelli S, Longaretti L, Perico L, Tomasoni S, Zoja C, Macconi D, Morigi M, Remuzzi G, Benigni A (2013) Angiotensin II contributes to diabetic renal dysfunction in rodents and humans via Notch1/Snail pathway. Am J Pathol 183:119–130. https://doi.org/10.1016/j.ajpath.2013.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cooper ME, Mundel P, Boner G (2002) Role of nephrin in renal disease including diabetic nephropathy. Semin Nephrol 22:393–398. https://doi.org/10.1053/snep.2002.34724

    Article  CAS  PubMed  Google Scholar 

  47. Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59:251–287. https://doi.org/10.1124/pr.59.3.3

    Article  CAS  PubMed  Google Scholar 

  48. Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther. https://doi.org/10.1038/sigtrans.2017.23

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wang W, Qiu L, Howard A, Solis N, Li C, Wang X, Kopp JB, Levi M (2014) Protective effects of aliskiren and valsartan in mice with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 15:384–395. https://doi.org/10.1177/1470320313507123

    Article  CAS  PubMed  Google Scholar 

  50. Wang S, Li Y, Miao W, Zhao H, Zhang F, Liu N, Su G, Cai X (2016) Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes. Mol Med Rep 14:2607–2613. https://doi.org/10.3892/mmr.2016.5544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Prof Laila Rashed, Biochemistry Department, Faculty of Medicine, Kasr Aini University. We also give our thanks to Dr. Mohamed K. El-Kherbetawy, Pathology Department, Faculty of Medicine, Suez Canal University.

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This research did not receive any specific grant from funding agencies.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Mona K. Tawfik

  2. Nephrology Division, Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Mohammed M. Keshawy

  3. Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Samy Makary

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  1. Mona K. Tawfik
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  2. Mohammed M. Keshawy
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  3. Samy Makary
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MKT: conceptualization, data curation, formal analysis, investigation, methodology. Project administration, resources, supervision, validation, visualization, writing—original draft, writing—review and editing. MMK: conceptualization, resources, validation, visualization, writing—original draft, writing—review and editing scientific writing. SM: conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing—original draft, writing—review and editing scientific writing.

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Correspondence to Mohammed M. Keshawy.

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Suez Canal University, faculty of medicine animal care committee (Research No. 4302).

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Tawfik, M.K., Keshawy, M.M. & Makary, S. Blocking angiotensin 2 receptor attenuates diabetic nephropathy via mitigating ANGPTL2/TL4/NF-κB expression. Mol Biol Rep 48, 6457–6470 (2021). https://doi.org/10.1007/s11033-021-06647-9

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