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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Effects of a New SGLT2 Inhibitor, Luseogliflozin, on Diabetic Nephropathy in T2DN Rats

Naoki Kojima, Jan M. Williams, Teisuke Takahashi, Noriyuki Miyata and Richard J. Roman
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 464-472; DOI: https://doi.org/10.1124/jpet.113.203869
Naoki Kojima
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (N.K., J.M.W., R.J.R.); and Molecular Function and Pharmacology Laboratories (N.K., T.T.), Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan
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Jan M. Williams
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (N.K., J.M.W., R.J.R.); and Molecular Function and Pharmacology Laboratories (N.K., T.T.), Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan
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Teisuke Takahashi
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (N.K., J.M.W., R.J.R.); and Molecular Function and Pharmacology Laboratories (N.K., T.T.), Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan
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Noriyuki Miyata
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (N.K., J.M.W., R.J.R.); and Molecular Function and Pharmacology Laboratories (N.K., T.T.), Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan
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Richard J. Roman
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (N.K., J.M.W., R.J.R.); and Molecular Function and Pharmacology Laboratories (N.K., T.T.), Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan
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Abstract

This study examined the effect of long-term control of hyperglycemia with a new sodium glucose cotransporter 2 inhibitor, luseogliflozin, given alone or in combination with lisinopril on the progression of renal injury in the T2DN rat model of type 2 diabetic nephropathy. Chronic treatment with luseogliflozin (10 mg/kg/day) produced a sustained increase in glucose excretion and normalized blood glucose and glycosylated hemoglobin levels to the same level as seen in the rats treated with insulin. It had no effect on blood pressure. In contrast, lisinopril (10 mg/kg/day) reduced mean blood pressure from 140 to 113 mmHg. Combination therapy significantly reduced blood pressure more than that seen in the rats treated with lisinopril. T2DN rats treated with vehicle exhibited progressive proteinuria, a decline in glomerular filtration rate (GFR), focal glomerulosclerosis, renal fibrosis, and tubular necrosis. Control of hyperglycemia with luseogliflozin prevented the fall in GFR and reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis. In contrast, control of hyperglycemia with insulin had no effect on the progression of renal disease in T2DN rats. Reducing blood pressure with lisinopril prevented the fall in GFR and reduced proteinuria and the degree of glomerular injury and tubular necrosis. Combination therapy reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis to a greater extent than administration of either drug alone. These results suggest that control of hyperglycemia with luseogliflozin slows the progression of diabetic nephropathy more than that seen with insulin, and combination therapy is more renoprotective than administration of either compound alone.

Footnotes

    • Received February 4, 2013.
    • Accepted March 13, 2013.
  • This research was funded in part by the National Institutes of Health [Grant HL36279]; and funds provided by a contract research agreement from Taisho Pharmaceutical Co., Ltd., Saitama, Japan, to evaluate the renal effects of Luseogliflozin.

  • A portion of this work was previously presented: Kojima N and Roman RJ (2012) Renoprotective effects of SGLT2 inhibitor, Luseogliflozin, on the progression of diabetic nephropathy in T2DN rats. 2012 High Blood Pressure Research Scientific Sessions; 2012 Sept 19; Washington, DC; and the abstract was published in Hypertension 2012; 60: A221.

  • dx.doi.org/10.1124/jpet.113.203869.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SGLT2 Inhibitors and Diabetic Nephropathy

Naoki Kojima, Jan M. Williams, Teisuke Takahashi, Noriyuki Miyata and Richard J. Roman
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 464-472; DOI: https://doi.org/10.1124/jpet.113.203869

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SGLT2 Inhibitors and Diabetic Nephropathy

Naoki Kojima, Jan M. Williams, Teisuke Takahashi, Noriyuki Miyata and Richard J. Roman
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 464-472; DOI: https://doi.org/10.1124/jpet.113.203869
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