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

Hare, Gregory M. T.; Zhang, Yanling; Chin, Kyle; Thai, Kerri; Jacobs, Evelyn; Cazorla-Bak, Melina P; Nghiem, Linda; Wilson, David F.; Vinogradov, Sergei A.; Connelly, Kim A.; Mazer, C. David; Evans, Roger G.; Gilbert, Richard E.

doi:10.14814/phy2.14890

Cited by 18 publications

(18 citation statements)

References 38 publications

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“…In a recent in vivo study in diabetic rats treated with dapagliflozin, a significant reduction in microvascular kidney oxygen tension was demonstrated in the deeper cortex and outer medulla, right where SGLT1 are primarily located, but not in the superficial cortex that includes few if any S3 segments. Consistent with this observation, hypoxia-responsive erythropoietin mRNA levels were elevated, and reticulocyte counts increased [ 342 ]. These findings likely reflect the interplay of the TGF-induced afferent arteriolar constriction, decreased sodium reabsorption in the early proximal tubule, and increased sodium reabsorption at the S3 segment PTCs.…”

Section: Effects Of Sglt2-is On Erythropoietin and Erythropoiesismentioning

confidence: 57%

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

Salvatore

Galiero

Caturano

et al. 2022

IJMS

128

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.

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Section: Effects Of Sglt2-is On Erythropoietin and Erythropoiesismentioning

confidence: 57%

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

Salvatore

Galiero

Caturano

et al. 2022

IJMS

128

View full text Add to dashboard Cite

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“…It has been hypothesized that the increased tubular workload related to increased distal sodium delivery after SGLT2 inhibition might produce renal medullary hypoxia, 58 thus triggering the synthesis of erythropoietin and an increase in hemoglobin. However, magnetic resonance imaging has not discerned evidence for the induction or alleviation of renal hypoxia in patients treated with SGLT2 inhibitors, 59 suggesting that the increase in erythropoietin is likely related to an effect on hypoxia-inducible factors.…”

Section: Potential Actions Of Sglt2 Inhibitors To Promote Energy Subs...mentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

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“…In the diabetic kidney, several previous reports, including ours, demonstrated that the pimonidazole-positive area expands towards the cortex, suggesting that proximal tubules are exposed to a more hypoxic environment [ 7 , 30 , 31 ]. However, recent reports using direct measurement of intravascular oxygen tension demonstrated that SGLT2 inhibition does not affect the microvascular oxygen tension in the superficial cortex, which proposed the concept of improvement of tissue hypoxia in the renal cortex by SGLT2 inhibitors [ 32 ]. The discrepancy among these findings may be explained by the following: First, pimonidazole does not reflect the microvascular oxygen tension faithfully because this probe is used for detecting the low intracellular oxygen concentration [ 25 ].…”

Section: Discussionmentioning

confidence: 99%