Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats

Badreldin Ali, Suhail Al Salam, Yousuf Al Suleimani, Mohammed A l Za'abi, Aly Abdelrahman, Mohammed Ashique, Priyadarsini Manoj, Sirin Adham, Christina Hartmann, Nicole Schupp, Abderrahim Nemmar

Research output: Contribution to journalArticle

Abstract

BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1β, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

Original languageEnglish
Pages (from-to)27-39
Number of pages13
JournalCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Volume52
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Adenine
Chronic Renal Insufficiency
Kidney
Creatinine
8-epi-prostaglandin F2alpha
Biomarkers
Indican
Urine
Clusterin
Cystatin C
Calcium Sulfate
Fatty Acid-Binding Proteins
Acetylglucosaminidase
Deoxyguanosine
Canagliflozin
Glutathione Reductase
Uric Acid
Interleukin-1
Pharmaceutical Preparations
Catalase

Keywords

  • Adenine
  • Canagliflozin
  • Chronic kidney disease
  • Rats

ASJC Scopus subject areas

  • Physiology

Cite this

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats. / Ali, Badreldin; Al Salam, Suhail; Al Suleimani, Yousuf; A l Za'abi, Mohammed; Abdelrahman, Aly; Ashique, Mohammed; Manoj, Priyadarsini; Adham, Sirin; Hartmann, Christina; Schupp, Nicole; Nemmar, Abderrahim.

In: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, Vol. 52, No. 1, 01.01.2019, p. 27-39.

Research output: Contribution to journalArticle

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AU - Al Salam, Suhail

AU - Al Suleimani, Yousuf

AU - A l Za'abi, Mohammed

AU - Abdelrahman, Aly

AU - Ashique, Mohammed

AU - Manoj, Priyadarsini

AU - Adham, Sirin

AU - Hartmann, Christina

AU - Schupp, Nicole

AU - Nemmar, Abderrahim

PY - 2019/1/1

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N2 - BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1β, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

AB - BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1β, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

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