Skip to main content

Advertisement

SpringerLink
Log in

Empagliflozin Attenuates Renal and Urinary Markers of Tubular Epithelial Cell Injury in Streptozotocin-induced Diabetic Rats

  • Original Research Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

Empagliflozin, a SGLT-2 inhibitor, improves diabetic nephropathy through its pleiotropic anti-inflammatory effects. The present study aims to evaluate empagliflozin effects on renal and urinary levels of tubular epithelial cell injury markers in streptozotocin-induced diabetic rats. Empagliflozin at 10 mg/kg (p.o.) was administered for 4 weeks, beginning 8 weeks after induction of diabetes. Renal function as well as markers of renal tubular epithelial cell injury were assessed in kidney tissue homogenates and urine. Empagliflozin was able to ameliorate diabetes induced elevations in serum cystatin C levels. It also alleviated renal KIM-1/NGAL levels and urinary albumin, α-GST, and RBP excretions. In addition to decreasing urinary levels of cell cycle arrest indices i.e. TIMP-2 and IGFBP7, empagliflozin mitigated acetylated NF-κB levels in renal tissues of diabetic rats. As a whole, these findings reveal empagliflozin capability in improving diabetic nephropathy via ameliorating indices of renal inflammation, injury, and cell cycle arrest on streptozotocin-induced diabetic rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

SGLT-2:

Sodium-glucose co-transporter 2

KIM-1:

Kidney injury molecule 1

NGAL:

Neutrophil gelatinase-associated lipocalin

KIM-1:

Kidney injury molecule-1

α-GST:

Alpha-glutathione S-transferase

RBP:

Retinol-binding protein

TIMP-2:

Tissue inhibitor of metalloproteinase 2

IGFBP7:

Insulin like growth factor binding protein 7

References

  1. Nichols GA, Vupputuri S, Lau H. Medical care costs associated with progression of diabetic nephropathy. Diabetes Care. 2011;34(11):2374–8.

    Article  Google Scholar 

  2. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137–88.

    Article  CAS  Google Scholar 

  3. Tervaert TWC, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556–63.

    Article  Google Scholar 

  4. Tang SC, Lai KN. The pathogenic role of the renal proximal tubular cell in diabetic nephropathy. Nephrol Dial Transplant. 2012;27(8):3049–56.

    Article  CAS  Google Scholar 

  5. Gæde P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.

    Article  Google Scholar 

  6. Zoungas S, De Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes. Diabetes Care. 2009;32(11):2068–74.

    Article  CAS  Google Scholar 

  7. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39.

    Article  CAS  Google Scholar 

  8. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–903.

    Article  CAS  Google Scholar 

  9. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J. 2017;39(5):363–70.

    Article  Google Scholar 

  10. Škrtic M, Cherney DZ. Sodium–glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24(1):96–103.

    Article  Google Scholar 

  11. Gallo LA, Ward MS, Fotheringham AK, Zhuang A, Borg DJ, Flemming NB, et al. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. Sci Rep. 2016;6:26428.

    Article  CAS  Google Scholar 

  12. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39(Supplement 2):S165–71.

    Article  CAS  Google Scholar 

  13. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.

    Article  CAS  Google Scholar 

  14. Lameire N, Vanmassenhove J, Van Biesen W, Vanholder R. The cell cycle biomarkers: promising research, but do not oversell them. Clin Kidney J. 2016;9(3):353–8.

    Article  CAS  Google Scholar 

  15. Tesauro M, Nisticò S, Noce A, Tarantino A, Marrone G, Costa A, et al. The possible role of glutathione-S-transferase activity in diabetic nephropathy. Int J Immunopathol Pharmacol. 2015;28(1):129–33.

    Article  CAS  Google Scholar 

  16. Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res. 2015;47(09):686–92.

    Article  CAS  Google Scholar 

  17. Chen S, Chen H, Liu Q, Ma Q. Effect of simvastatin on the expression of nephrin, podocin, and vascular endothelial growth factor (VEGF) in podocytes of diabetic rat. Int J Clin Exp Med. 2015;8(10):18225.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Randers E, Kristensen H, Erlandsen EJ, Danielsen S. Serum cystatin C as a marker of the renal function. Scand J Clin Lab Investig. 1998;58(7):585–92.

    Article  CAS  Google Scholar 

  19. Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015;11(5):264.

    Article  CAS  Google Scholar 

  20. Kashani K, Kellum JA. Novel biomarkers indicating repair or progression after acute kidney injury. Curr Opin Nephrol Hypertens. 2015;24(1):21–7.

    Article  CAS  Google Scholar 

  21. Kellum JA. Diagnostic criteria for acute kidney injury: present and future. Crit Care Clin. 2015;31(4):621–32.

    Article  Google Scholar 

  22. Watanabe J, Takiyama Y, Honjyo J, Makino Y, Fujita Y, Tateno M, et al. Role of IGFBP7 in diabetic nephropathy: TGF-β1 induces IGFBP7 via Smad2/4 in human renal proximal tubular epithelial cells. PLoS ONE. 2016;11(3):e0150897.

    Article  Google Scholar 

  23. Xu X, Xiao L, Xiao P, Yang S, Chen G, Liu F, et al. A glimpse of matrix metalloproteinases in diabetic nephropathy. Curr Med Chem. 2014;21(28):3244–60.

    Article  CAS  Google Scholar 

  24. Tramonti G, Kanwar YS. Tubular biomarkers to assess progression of diabetic nephropathy. Kidney Int. 2011;79(10):1042–4.

    Article  CAS  Google Scholar 

  25. Titan S, Vieira J, Dominguez W, Moreira S, Pereira A, Barros R, et al. Urinary MCP-1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy. J Diabetes Complicat. 2012;26(6):546–53.

    Article  CAS  Google Scholar 

  26. Gembardt F, Bartaun C, Jarzebska N, Mayoux E, Todorov VT, Hohenstein B, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307(3):F317–25.

    Article  CAS  Google Scholar 

  27. Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS ONE. 2014;9(6):e100777.

    Article  Google Scholar 

  28. Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? PLoS ONE. 2013;8(2):e54442.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This investigation is a supported by grants from Student Research center and Biotechnology Research Center, Tabriz University of Medical Sciences; and Urology and Nephrology Research Center, Beheshti University of Medical Sciences, Tehran, Iran.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Ashrafi Jigheh, Davoud Sanajou, Saeed Nazari Soltan Ahmad & Jalil Rashedi

  2. Student Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Ashrafi Jigheh

  3. Biotechnology Research Center, Tabriz University of Medical Sciences, Goshgasht Avenue, PO BOX: 14711, Tabriz, 5166614711, Iran

    Amir Ghorbani Haghjo, Nadereh Rashtchizadeh & Siavoush Dastmalchi

  4. Urology and Nephrology Research Center, Beheshti University of Medical Sciences, Tehran, Iran

    Hassan Argani

  5. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Leila Roshangar

  6. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mehran Mesgari Abbasi

Authors
  1. Zahra Ashrafi Jigheh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amir Ghorbani Haghjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hassan Argani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leila Roshangar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nadereh Rashtchizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Davoud Sanajou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saeed Nazari Soltan Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jalil Rashedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Siavoush Dastmalchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mehran Mesgari Abbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amir Ghorbani Haghjo.

Ethics declarations

Conflicts of interest

None of the authors declare any conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashrafi Jigheh, Z., Ghorbani Haghjo, A., Argani, H. et al. Empagliflozin Attenuates Renal and Urinary Markers of Tubular Epithelial Cell Injury in Streptozotocin-induced Diabetic Rats. Ind J Clin Biochem 35, 109–114 (2020). https://doi.org/10.1007/s12291-018-0790-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-018-0790-6

Keywords

Search

Navigation