TY - JOUR
T1 - Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus
AU - Hare, Gregory M.T.
AU - Zhang, Yanling
AU - Chin, Kyle
AU - Thai, Kerri
AU - Jacobs, Evelyn
AU - Cazorla-Bak, Melina P.
AU - Nghiem, Linda
AU - Wilson, David F.
AU - Vinogradov, Sergei A.
AU - Connelly, Kim A.
AU - Mazer, C. David
AU - Evans, Roger G.
AU - Gilbert, Richard E.
N1 - Funding Information:
Funding for this study was contributed, in part, by an investigator‐initiated grant from Astra Zeneca that had no part in the design, conduct, writing or interpretation of the study. REG reports receiving other research grants to his institution from AstraZeneca and Boehringer Ingelheim; serving on advisory panels for AstraZeneca, Boehringer Ingelheim, and Janssen; receiving CME speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen, all unrelated to the current study. He also reports being a shareholder in Certa Therapeutics, OccuRx and Fibrocor Therapeutics and is CSO of Fibrocor Therapeutics. KAC reports receiving research grants to his institution from AstraZeneca and Boehringer Ingelheim; serving on advisory panels for AstraZeneca, Boehringer Ingelheim, and Janssen; receiving CME speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen, all unrelated to the current study. RGE reports receiving consulting fees from Medtronic Inc, unrelated to the current study.
Funding Information:
Support for this study was provided by investigator-initiated grants from the Morris A. Hunter Charitable trust and Astra Zeneca, RE Gilbert; RE Gilbert holds a Canada Research Chair, this study was made possible by the Canada Research Chair's fund. University of Toronto Merit Awards supported Drs. KA Connelly, GMT Hare, and CD Mazer. GMT Hare received support from the SMH AFP Innovation Fund. SA Vinogradov received support from the National Institute of Health, grant U24EB028941 USA, which is gratefully acknowledged. The CAS RA Gordon Award supported this research.
Funding Information:
Support for this study was provided by investigator‐initiated grants from the Morris A. Hunter Charitable trust and Astra Zeneca, RE Gilbert; RE Gilbert holds a Canada Research Chair, this study was made possible by the Canada Research Chair's fund. University of Toronto Merit Awards supported Drs. KA Connelly, GMT Hare, and CD Mazer. GMT Hare received support from the SMH AFP Innovation Fund. SA Vinogradov received support from the National Institute of Health, grant U24EB028941 USA, which is gratefully acknowledged. The CAS RA Gordon Award supported this research.
Publisher Copyright:
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.
AB - Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.
UR - http://www.scopus.com/inward/record.url?scp=85108817813&partnerID=8YFLogxK
U2 - 10.14814/phy2.14890
DO - 10.14814/phy2.14890
M3 - Article
C2 - 34184431
AN - SCOPUS:85108817813
SN - 2051-817X
VL - 9
JO - Physiological Reports
JF - Physiological Reports
IS - 12
M1 - e14890
ER -
