Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy
Abstract Oxidative stress and apoptosis are highly engaged in development of diabetic nephropathy (DN). In monotherapy, dapagliflozin and pioglitazone positively modulate target organ damage even independently of their hypoglycaemic effect. This study evaluated whether a simultaneous PPARγ activatio...
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Nature Portfolio
2025-01-01
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| author | Aneta Cinakova Diana Vavrincova-Yaghi Peter Krenek Jan Klimas Eva Kralova |
| author_facet | Aneta Cinakova Diana Vavrincova-Yaghi Peter Krenek Jan Klimas Eva Kralova |
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| description | Abstract Oxidative stress and apoptosis are highly engaged in development of diabetic nephropathy (DN). In monotherapy, dapagliflozin and pioglitazone positively modulate target organ damage even independently of their hypoglycaemic effect. This study evaluated whether a simultaneous PPARγ activation and SGLT cotransporter inhibition offer superior protection against DN-related oxidative and apoptotic processes in a T1DM rat model. Diabetes was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). The rats received daily chow containing dapagliflozin (10 mg/kg), pioglitazone (12 mg/kg) or their combination. Six weeks after STZ administration, histological and molecular analyses were performed in excised kidneys. STZ-induced DN was demonstrated by the propagation of apoptotic (Bax, p53, Casp3) and oxidative reactions (Gp91phox, MnSOD) and disrupted nitric oxide signalling (eNOS, Hsp90, Cav1). Kidney damage molecule expression (Kim1, Nphs1) revealed a deceleration of kidney damage by pioglitazone and dapagliflozine monotherapies. The monotherapy also reduced apoptosis, oxidative stress, and partially restored NO signalling. The combined therapy ameliorated glomerulosclerosis but in other measured parameters, it reached the effect of the monotherapies except for Hsp90 expression modulation. Both dapagliflozin and pioglitazone exert protective character in kidneys when used in monotherapy. The combined therapy does not exhibit an expected additive effect within modulating oxidative stress, NO signalling or apoptosis. |
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| institution | Kabale University |
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| language | English |
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| spelling | doaj-art-6a4ea3ba073f4018a74e25bcc16bbc412025-01-12T12:22:53ZengNature PortfolioScientific Reports2045-23222025-01-0115111110.1038/s41598-024-84487-wCombination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathyAneta Cinakova0Diana Vavrincova-Yaghi1Peter Krenek2Jan Klimas3Eva Kralova4Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University BratislavaFaculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University BratislavaFaculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University BratislavaFaculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University BratislavaFaculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University BratislavaAbstract Oxidative stress and apoptosis are highly engaged in development of diabetic nephropathy (DN). In monotherapy, dapagliflozin and pioglitazone positively modulate target organ damage even independently of their hypoglycaemic effect. This study evaluated whether a simultaneous PPARγ activation and SGLT cotransporter inhibition offer superior protection against DN-related oxidative and apoptotic processes in a T1DM rat model. Diabetes was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). The rats received daily chow containing dapagliflozin (10 mg/kg), pioglitazone (12 mg/kg) or their combination. Six weeks after STZ administration, histological and molecular analyses were performed in excised kidneys. STZ-induced DN was demonstrated by the propagation of apoptotic (Bax, p53, Casp3) and oxidative reactions (Gp91phox, MnSOD) and disrupted nitric oxide signalling (eNOS, Hsp90, Cav1). Kidney damage molecule expression (Kim1, Nphs1) revealed a deceleration of kidney damage by pioglitazone and dapagliflozine monotherapies. The monotherapy also reduced apoptosis, oxidative stress, and partially restored NO signalling. The combined therapy ameliorated glomerulosclerosis but in other measured parameters, it reached the effect of the monotherapies except for Hsp90 expression modulation. Both dapagliflozin and pioglitazone exert protective character in kidneys when used in monotherapy. The combined therapy does not exhibit an expected additive effect within modulating oxidative stress, NO signalling or apoptosis.https://doi.org/10.1038/s41598-024-84487-wDiabetic nephropathyRatDapagliflozinPioglitazoneDiabetes mellitus |
| spellingShingle | Aneta Cinakova Diana Vavrincova-Yaghi Peter Krenek Jan Klimas Eva Kralova Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy Scientific Reports Diabetic nephropathy Rat Dapagliflozin Pioglitazone Diabetes mellitus |
| title | Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy |
| title_full | Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy |
| title_fullStr | Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy |
| title_full_unstemmed | Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy |
| title_short | Combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin-induced nephropathy |
| title_sort | combination of dapagliflozin and pioglitazone lacks superiority against monotherapy in streptozotocin induced nephropathy |
| topic | Diabetic nephropathy Rat Dapagliflozin Pioglitazone Diabetes mellitus |
| url | https://doi.org/10.1038/s41598-024-84487-w |
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