Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Abstract

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury. Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury. Lay SummaryThe underlying mechanism by which sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure in patients with type 2 diabetes (T2D) is incompletely understood. In a large clinical trial of patients with T2D, we observed that each increment in urinary epidermal growth factor (EGF) is associated with a lower risk of kidney failure. In kidney biopsies, we observed that EGF expression was significantly lower in young persons with T2D compared with that in healthy controls, whereas EGF expression in young persons with T2D on SGLT2 inhibitors was closer to the level observed in HCs. Collectively, these data support a role for EGF in the kidney-protective effect of SGLT2 inhibitors, and they suggest that EGF may be used as a pharmacodynamic marker of response to SGLT2 inhibition. The underlying mechanism by which sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure in patients with type 2 diabetes (T2D) is incompletely understood. In a large clinical trial of patients with T2D, we observed that each increment in urinary epidermal growth factor (EGF) is associated with a lower risk of kidney failure. In kidney biopsies, we observed that EGF expression was significantly lower in young persons with T2D compared with that in healthy controls, whereas EGF expression in young persons with T2D on SGLT2 inhibitors was closer to the level observed in HCs. Collectively, these data support a role for EGF in the kidney-protective effect of SGLT2 inhibitors, and they suggest that EGF may be used as a pharmacodynamic marker of response to SGLT2 inhibition. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) block reabsorption of sodium and glucose in the proximal tubule. Large clinical trials have shown that SGLT2i slow the progression of kidney function decline and reduce the risk of kidney failure in patients with chronic kidney disease (CKD) with and without type 2 diabetes (T2D).1Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (3224) Google Scholar, 2Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2519) Google Scholar, 3Neuen B.L. Young T. Heerspink H.J.L. et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2019; 7: 845-854Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 4Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1931) Google Scholar The mechanisms contributing to these protective effects are understood incompletely, but they likely involve various pathways. including attenuation of intraglomerular hyperfiltration, amelioration of hypoxia, reduction in inflammation metabolic reprogramming promoting autophagy, and mitophagy.5Sen T. Heerspink H.J.L. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors.Cell Metab. 2021; 33: 732-739Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Epidermal growth factor (EGF) is a key mitogenic factor involved in cell proliferation, hypertrophy, migration, and differentiation of epithelial cells.6Wee P. Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways.Cancers (Basel). 2017; 9: 52Crossref PubMed Scopus (966) Google Scholar,7Ju W. Nair V. Smith S. et al.Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.Sci Transl Med. 2015; 7: 316ra193Crossref PubMed Scopus (254) Google Scholar EGF is produced predominantly in the ascending loop of Henle and the distal convoluted tubule (DCT), and it exerts its effect to the EGF which is expressed in the kidney the the loop of the and the W. Nair V. Smith S. et al.Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.Sci Transl Med. 2015; 7: 316ra193Crossref PubMed Scopus (254) Google Scholar have decreased of urinary EGF in kidney including in patients with T2D and B. Epidermal growth factor and kidney a Full Text Full Text PDF PubMed Scopus Google Scholar the EGF level measured in tissue from kidney biopsies of patients with uEGF and is associated with kidney outcomes and kidney disease W. Nair V. Smith S. et al.Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.Sci Transl Med. 2015; 7: 316ra193Crossref PubMed Scopus (254) Google et in a of epidermal growth factor as a for renal in patients with type 2 Full Text Full Text PDF PubMed Scopus Google Scholar suggest that EGF a role in promoting kidney injury. the effects of SGLT2i on uEGF in clinical have to be examined. in we assessed baseline uEGF by (uEGF/Cr) is associated with kidney outcomes in patients with T2D at cardiovascular risk in the Canagliflozin Assessment Study (CANVAS) we the SGLT2i canagliflozin increased the of uEGF/Cr in the we the molecular mechanisms for SGLT2 uEGF using single-cell RNA sequencing from kidney biopsies from young persons with T2D were and were not using SGLT2i from the and in 2 Diabetes Study and the on and in with 2 Diabetes The trial was a clinical trial that assessed the and of the SGLT2i canagliflozin on cardiovascular and kidney outcomes in participants with T2D were at cardiovascular risk a of cardiovascular of trial have B. 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Smith S. et al.Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.Sci Transl Med. 2015; 7: 316ra193Crossref PubMed Scopus (254) Google Scholar EGF kidney tubular cell and repair and the of kidney function in of kidney its protective role in kidney tubular cell et growth factor renal tubule cell and repair and the of renal function in renal PubMed Scopus Google Scholar, Epidermal growth factor renal repair in J Google Scholar, Epidermal growth factor from tubular in the role of the epidermal growth factor PubMed Scopus Google Scholar, et growth factor renal tissue repair in a of in J Google Scholar, et EGF as a factor in renal J Google Scholar, V. et of renal EGF and to PubMed Scopus (62) Google Scholar, T. et growth factor tubular by of not Med. 2015; PubMed Scopus Google Scholar In the a significantly level of EGF mRNA was observed in of young persons with T2D using standard of compared to that of tissue from healthy for repair of that EGF may function as a regulator in distal tubular by the downstream of which role in kidney repair and are with kidney function in patients with W. 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