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Renoprotective effects of empagliflozin in type 1 and type 2 models of diabetic nephropathy superimposed with hypertension

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Abstract

Diabetes, hypertension, and aging are major contributors to cardiovascular and chronic kidney disease (CKD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors have become a preferred treatment for type II diabetic patients since they have cardiorenal protective effects. However, most elderly diabetic patients also have hypertension, and the effects of SGLT2 inhibitors have not been studied in hypertensive diabetic patients or animal models. The present study examined if controlling hyperglycemia with empagliflozin, or given in combination with lisinopril, slows the progression of renal injury in hypertensive diabetic rats. Studies were performed using hypertensive streptozotocin-induced type 1 diabetic Dahl salt-sensitive (STZ-SS) rats and in deoxycorticosterone-salt hypertensive type 2 diabetic nephropathy (T2DN) rats. Administration of empagliflozin alone or in combination with lisinopril reduced blood glucose, proteinuria, glomerular injury, and renal fibrosis in STZ-SS rats without altering renal blood flow (RBF) or glomerular filtration rate (GFR). Blood pressure and renal hypertrophy were also reduced in rats treated with empagliflozin and lisinopril. Administration of empagliflozin alone or in combination with lisinopril lowered blood glucose, glomerulosclerosis, and renal fibrosis but had no effect on blood pressure, kidney weight, or proteinuria in hypertensive T2DN rats. RBF was not altered in any of the treatment groups, and GFR was elevated in empagliflozin-treated hypertensive T2DN rats. These results indicate that empagliflozin is highly effective in controlling blood glucose levels and slows the progression of renal injury in both hypertensive type 1 and type 2 diabetic rats, especially when given in combination with lisinopril to lower blood pressure.

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Copies of data files, images presented in this manuscript, and breeding pairs of the animal strains used will be made available upon written request and after a Material Transfer Agreement is completed by both institutions.

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Funding

This study was partially supported by grants DK109133, AG057842, P20GM104357, and HL138685 from the National Institutes of Health and a collaborative research agreement DE 811138149 from Boehringer Ingelheim International GmbH. The views expressed in this manuscript are expressly those of the author(s) and were not influenced by the funding institutions.

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  1. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA

    Jan M. Williams, Sydney R. Murphy, Wenjie Wu, Jane J. Border, Fan Fan & Richard J. Roman

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Contributions

R.J.R conceived and designed research; S.R.M., J.M.W., and W.W. performed experiments; J.M.W., S.R.M., W.W., J.J.B., F.F., and R.J.R analyzed data; J.M.W., F.F., and R.J.R interpreted results of experiments; S.R.M., J.J.B., and F.F. prepared figures; J.M.W. and F.F. drafted the manuscript. All authors contributed to the article and approved the final version of the manuscript.

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Correspondence to Richard J. Roman.

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This study utilized Dahl salt-sensitive and type 2 diabetic nephropathy rats that were obtained from in-house colonies in the Laboratory Animal Facility at the University of Mississippi Medical Center, which is approved by the American Association for the Accreditation of Laboratory Animal Care. All of the animal studies were performed in accordance with the US Public Health Service Policy on the Care and Use of Laboratory Animals and were approved by the Animal Care Committee of the University of Mississippi Medical Center.

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Williams, J.M., Murphy, S.R., Wu, W. et al. Renoprotective effects of empagliflozin in type 1 and type 2 models of diabetic nephropathy superimposed with hypertension. GeroScience 44, 2845–2861 (2022). https://doi.org/10.1007/s11357-022-00610-7

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