Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

被引：21

作者：

Hare, Gregory M. T. ^{[1
,3
,4
]}

Zhang, Yanling ^{[4
]}

Chin, Kyle ^{[3
]}

Thai, Kerri ^{[4
]}

Jacobs, Evelyn

Cazorla-Bak, Melina P. ^{[3
]}

Nghiem, Linda ^{[4
]}

Wilson, David F. ^{[5
]}

Vinogradov, Sergei A. ^{[5
]}

Connelly, Kim A. ^{[3
,6
]}

Mazer, C. David ^{[3
,4
,7
]}

Evans, Roger G. ^{[8
,9
]}

Gilbert, Richard E. ^{[2
,4
,10
]}

机构：

[1] Univ Toronto, Dept Anesthesia, St Michaels Hosp, Toronto, ON M5B 1W8, Canada

[2] St Michaels Hosp, Div Endocrinol, Dept Med, 30 Bond St, Toronto, ON M5B 1W8, Canada

[3] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[4] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada

[5] Univ Pennsylvania, Sch Med, Dept Biochem & Biophys, Philadelphia, PA USA

[6] Univ Toronto, St Michaels Hosp, Div Cardiol, Dept Med, Toronto, ON, Canada

[7] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[8] Monash Univ, Biomed Discovery Inst, Cardiovasc Dis Program, Melbourne, Vic, Australia

[9] Monash Univ, Dept Physiol, Melbourne, Vic, Australia

[10] Univ Toronto, St Michaels Hosp, Div Endocrinol, Dept Med, Toronto, ON, Canada

来源：

PHYSIOLOGICAL REPORTS | 2021年 / 9卷 / 12期

关键词：

THERAPEUTIC TARGET; HYPOXIA; EMPAGLIFLOZIN; CANAGLIFLOZIN; CONSUMPTION; MORTALITY;

D O I：

10.14814/phy2.14890

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

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.

引用

页数：16

共 41 条

[1] Renal tissue PO2 sensing during acute hemodilution is dependent on the diluent [J].

Abrahamson, Jessica R. ;

Read, Austin ;

Chin, Kyle ;

Mistry, Nikhil ;

Joo, Hannah ;

Desjardins, Jean-Francois ;

Liu, Elaine ;

Thai, Kerri ;

Wilson, David F. ;

Vinogradov, Sergei A. ;

Maynes, Jason T. ;

Gilbert, Richard E. ;

Connelly, Kim A. ;

Baker, Andrew J. ;

Mazer, C. David ;

Hare, Gregory M. T. .

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2020, 318 (04) :R799-R812

[2] Effect of wavelength and beam width on penetration in light-tissue interaction using computational methods [J].

Ash, Caerwyn ;

Dubec, Michael ;

Donne, Kelvin ;

Bashford, Tim .

LASERS IN MEDICAL SCIENCE, 2017, 32 (08) :1909-1918

[3] Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox? [J].

Ast, Tslil ;

Mootha, Vamsi K. .

NATURE METABOLISM, 2019, 1 (09) :858-860

[4] Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy [J].

Bessho, Ryoichi ;

Takiyama, Yumi ;

Takiyama, Takao ;

Kitsunai, Hiroya ;

Takeda, Yasutaka ;

Sakagami, Hidemitsu ;

Ota, Tsuguhito .

SCIENTIFIC REPORTS, 2019, 9 (1)

[5]

Chang YK, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0158810

[6] SGLT2 inhibition - a novel strategy for diabetes treatment [J].

Chao, Edward C. ;

Henry, Robert R. .

NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (07) :551-559

[7]

Chin K, 2021, CAN J ANESTH, V68, P214, DOI 10.1007/s12630-020-01848-5

[8] Two New "Protected" Oxyphors for Biological Oximetry: Properties and Application in Tumor Imaging [J].

Esipova, Tatiana V. ;

Karagodov, Alexander ;

Miller, Joann ;

Wilson, David F. ;

Busch, Theresa M. ;

Vinogradov, Sergei A. .

ANALYTICAL CHEMISTRY, 2011, 83 (22) :8756-8765

[9] Basal renal O2 consumption and the efficiency of O2 utilization for Na+ reabsorption [J].

Evans, Roger G. ;

Harrop, Gerard K. ;

Ngo, Jennifer P. ;

Ow, Connie P. C. ;

O'Connor, Paul M. .

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2014, 306 (05) :F551-F560

[10]

Fenton R., 2016, BRENNER RECTORS KIDN, P42

← 1 2 3 4 5 →