Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery

Franzén, Stephanie; Palm, Fredrik

doi:10.1007/s00125-015-3690-9

Cited by 5 publications

(6 citation statements)

References 45 publications

(52 reference statements)

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“…ETB-R are essential for the regulation of tubular sodium and water handling (11), and activation of ETB-R inhibits Na ϩ reabsorption via endothelial sodium channels in the distal parts of the nephron (16,24). The results from the present study demonstrate that acute activation of ETB-R improves intrarenal tissue PO 2 in the diabetic kidney similar to the previously reported effect of ETA-R blockade (3). It might therefore be beneficial to directly target ETB-R to improve tissue PO 2 in the diabetic kidney and concomitantly avoid unwanted fluid retention commonly observed in the clinical trials using ETA-R antagonists.…”

Section: Discussionsupporting

confidence: 89%

“…Surgical procedures. Fourteen days after induction of diabetes, all rats were prepared for measurements of kidney function and oxygen metabolism as previously described (3). In brief, anesthesia was induced using thiobutabarbital (120 mg/kg ip; Inactin), and body temperature was maintained at 37.5°C using a servo-controlled heating pad.…”

Section: Methodsmentioning

confidence: 99%

“…Tracheostomy was performed to facilitate spontaneous ventilation. Catheters were inserted into the carotid artery for monitoring of mean arterial blood pressure (MAP), into the jugular vein for infusion of [ 3 Louis, MO) and into the bladder to allow drainage. The left kidney was immobilized in a plastic cup, and the left ureter was catheterized to collect urine for subsequent measurements of kidney function.…”

Section: Methodsmentioning

confidence: 99%

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Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats

Franzén

Pihl

Fasching

et al. 2018

American Journal of Physiology-Renal Physiology

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About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats

Franzén

Pihl

Fasching

et al. 2018

American Journal of Physiology-Renal Physiology

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“…This discrepancy could signify that diabetes elicits a larger increase in basal Q O 2 than what we have assumed. On the other hand, our prediction that total Q O 2 is twice as high in diabetic rats as in control rats agrees well with the experimental results of Körner et al (25) and recent data from Palm and colleagues (17,30).…”

Section: Comparison With In Vivo Datasupporting

confidence: 91%

“…While some studies indicate that cortical, but not medullary, PO 2 is lower in diabetic rats than in control rats (17,34), others have found that PO 2 is reduced both in the cortex and medulla in diabetic rats (30). Whether medullary PO 2 in diabetic rats (about 15-20 mmHg) is sufficiently low to slow down active transport processes is not clear.…”

Section: Model Limitationsmentioning

confidence: 95%

Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

Layton

Vallon

Edwards

2016

American Journal of Physiology-Renal Physiology

123

155

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Diabetes increases the reabsorption of Na(+) (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments.

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Interacting hypoxia and endothelin in the diabetic kidney: therapeutic options

Heyman¹,

Khamaisi

Abassi

2018

American Journal of Physiology-Renal Physiology

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Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery

Cited by 5 publications

References 45 publications

Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats

Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats

Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

Interacting hypoxia and endothelin in the diabetic kidney: therapeutic options

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