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Horm Metab Res 2015; 47(09): 686-692
DOI: 10.1055/s-0034-1395609
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Empagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2 Exerts Anti-Inflammatory and Antifibrotic Effects on Experimental Diabetic Nephropathy Partly by Suppressing AGEs-Receptor Axis

A. Ojima
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
T. Matsui
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
Y. Nishino
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
N. Nakamura
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
S. Yamagishi
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
› Author Affiliations
Further Information

Publication History

received 20 September 2014

accepted 03 November 2014

Publication Date:
22 January 2015 (online)

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Abstract

Advanced glycation end products (AGEs) and receptor RAGE play a role in diabetic nephropathy. We have previously shown that increased glucose uptake into proximal tubular cells via sodium-glucose cotransporter 2 (SGLT2) stimulates oxidative stress generation and RAGE expression, thereby exacerbating the AGE-induced apoptosis in this cell type. However, the protective role of SGLT2 inhibition against the AGE-RAGE-induced renal damage in diabetic animals remains unclear. In this study, we investigated the effects of empagliflozin, SGLT2 inhibitor on AGE-RAGE axis, inflammatory and fibrotic reactions, and tubular injury in the kidney of streptozotocin-induced diabetic rats.

Administration of empagliflozin for 4 weeks significantly improved hyperglycemia and HbA1c, and decreased expression levels of AGEs, RAGE, 8-hydroxydeoxyguanosine (8-OHdG), and F4/80, markers of oxidative stress and macrophages, respectively, in the diabetic kidney. Although empagliflozin did not reduce albuminuria, it significantly decreased urinary excretion levels of 8-OHdG and L-fatty acid binding protein, a marker of tubular injury. Moreover, inflammatory and fibrotic gene expression such as monocyte chemoattractant protein-1, intercellular adhesion molecule-1, plasminogen activator inhibitor-1, transforming growth factor-β, and connective tissue growth factor was enhanced in the diabetic kidney, all of which were prevented by empagliflozin. The present study suggests that empagliflozin could inhibit oxidative, inflammatory and fibrotic reactions in the kidney of diabetic rats partly via suppression of the AGE-RAGE axis. Blockade of the increased glucose uptake into renal proximal tubular cells by empagliflozin might be a novel therapeutic target for tubulointerstitial damage in diabetic nephropathy.

Key words

AGEs - RAGE - diabetic nephropathy - oxidative stress - SGLT2
 

  • References

  • 1 Yamagishi S, Fukami K, Ueda S, Okuda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 2007; 8: 952-959
    CrossrefPubMedSearch in Google Scholar
  • 2 Karnib HH, Ziyadeh FN. The cardiorenal syndrome in diabetes mellitus. Diabetes Res Clin Pract 2010; 89: 201-208
    CrossrefPubMedSearch in Google Scholar
  • 3 Alsaad KO, Herzenberg AM. Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. J Clin Pathol 2007; 60: 18-26
    CrossrefPubMedSearch in Google Scholar
  • 4 Taft JL, Nolan CJ, Yeung SP, Hewitson TD, Martin FI. Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria. Diabetes 1994; 43: 1046-1051
    CrossrefPubMedSearch in Google Scholar
  • 5 Ziyadeh FN, Goldfarb S. The renal tubulointerstitium in diabetes mellitus. Kidney Int 1991; 39: 464-475
    CrossrefPubMedSearch in Google Scholar
  • 6 Vlassara H, Bucala R. Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors. Diabetes 1996; (Suppl. 03) S65-S66
    PubMedSearch in Google Scholar
  • 7 Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988; 318: 1315-1321
    CrossrefPubMedSearch in Google Scholar
  • 8 Rahbar S. Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys 2007; 48: 147-157
    CrossrefPubMedSearch in Google Scholar
  • 9 Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, Watanabe T, Yamagishi S, Sakurai S, Takasawa S, Okamoto H, Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest 2001; 108: 261-268
    CrossrefPubMedSearch in Google Scholar
  • 10 Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D’Agati VD, Schmidt AM. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003; 162: 1123-1137
    CrossrefPubMedSearch in Google Scholar
  • 11 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 2005; 11: 2279-2299
    CrossrefPubMedSearch in Google Scholar
  • 12 Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T. Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des 2008; 14: 487-495
    CrossrefPubMedSearch in Google Scholar
  • 13 Forbes JM, Cooper ME. Glycation in diabetic nephropathy. Amino Acids 2012; 42: 1185-1192
    CrossrefPubMedSearch in Google Scholar
  • 14 Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, Fukami K, Yamagishi S. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol 2013; 182: 132-141
    CrossrefPubMedSearch in Google Scholar
  • 15 Maeda S, Matsui T, Takeuchi M, Yoshida Y, Yamakawa R, Fukami K, Yamagishi S. Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis. Pharmacol Res 2011; 63: 241-248
    CrossrefPubMedSearch in Google Scholar
  • 16 Matsui T, Yamagishi S, Takeuchi M, Ueda S, Fukami K, Okuda S. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation. Biochem Biophys Res Commun 2010; 398: 326-330
    CrossrefPubMedSearch in Google Scholar
  • 17 Lee YJ, Lee YJ, Han HJ. Regulatory mechanims of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int 2007; 72: 527-535
    CrossrefPubMedSearch in Google Scholar
  • 18 Sabolic I, Vrhovac I, Eror DB, Gerasimova M, Rose M, Breljak D, Ljubojevic M, Brzica H, Sebastiani A, Thal SC, Sauvant C, Kipp H, Vallon V, Koepsell H. Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol 2012; 302: C1174-C1188
    CrossrefPubMedSearch in Google Scholar
  • 19 Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010; 5: 133-141
    CrossrefPubMedSearch in Google Scholar
  • 20 Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223-2233
    CrossrefPubMedSearch in Google Scholar
  • 21 Maeda S, Matsui T, Takeuchi M, Yamagishi S. Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab Res Rev 2013; 29: 406-412
    CrossrefPubMedSearch in Google Scholar
  • 22 Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo. Mol Med 2000; 6: 114-125
    PubMedSearch in Google Scholar
  • 23 Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, Pollock C, Mather A. Effects of SGLT2 inhibition in human kidney proximal tubular cells – renoprotection in diabetic nephropathy?. PLoS One 2013; 8: e54442
    CrossrefPubMedSearch in Google Scholar
  • 24 Osorio H, Coronel I, Arellano A, Pacheco U, Bautista R, Franco M, Escalante B. Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev. 2012; 542042
    PubMedSearch in Google Scholar
  • 25 Morrisey K, Steadman R, Williams JD, Phillips AO. Renal proximal tubular cell fibronectin accumulation in response to glucose is polyol pathway dependent. Kidney Int 1999; 55: 160-167
    CrossrefPubMedSearch in Google Scholar
  • 26 Gilbert RE. Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering?. Kidney Int 2014; 86: 693-700
    CrossrefPubMedSearch in Google Scholar
  • 27 Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol 2013; 304: F156-F167
    CrossrefPubMedSearch in Google Scholar
  • 28 Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014; 306: F194-F204
    CrossrefPubMedSearch in Google Scholar
  • 29 Matsui T, Yamagishi S, Takeuchi M, Ueda S, Fukami K, Okuda S. Irbesartan inhibits advanced glycation end product (AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression. Pharmacol Res 2010; 61: 34-39
    CrossrefPubMedSearch in Google Scholar
  • 30 Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression. Horm Metab Res 2012; 44: 891-895
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Chung AC, Zhang H, Kong YZ, Tan JJ, Huang XR, Kopp JB, Lan HY. Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling. J Am Soc Nephrol 2010; 21: 249-260
    CrossrefPubMedSearch in Google Scholar
  • 32 Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Renal Physiol 2011; 300: R1009-R1022
    PubMedSearch in Google Scholar
  • 33 Albertoni Borghese MF, Majowicz MP, Ortiz MC, Passalacqua Mdel R, Sterin Speziale NB, Vidal NA. Expression and activity of SGLT2 in diabetes induced by streptozotocin: relationship with the lipid environment. Nephron Physiol 2009; 112: 45-52
    CrossrefPubMedSearch in Google Scholar
  • 34 Osorio H, Coronel I, Arellano A, Franco M, Escalante B, Bautista R. Ursodeoxycholic acid decreases sodium-glucose cotransporter (SGLT2) expression and oxidative stress in the kidney of diabetic rats. Diabetes Res Clin Pract 2012; 97: 276-282
    CrossrefPubMedSearch in Google Scholar
  • 35 Abdul-Ghani YMA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes 2013; 62: 3324-3328
    CrossrefPubMedSearch in Google Scholar
  • 36 Powell DR, DaCosta CM, Gay J, Ding ZM, Smith M, Greer J, Doree D, Jeter-Jones S, Mseeh F, Rodriguez LA, Harris A, Buhring L, Platt KA, Vogel P, Brommage R, Shadoan MK, Sands AT, Zambrowicz B. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab 2013; 304: E117-E130
    CrossrefPubMedSearch in Google Scholar