O'Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O 2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol 309: F227-F234, 2015. First published June 3, 2015 doi:10.1152/ajprenal.00689.2014.-Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue PO 2. Recent observations have indicated that increased tubular Na ϩ -glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon PO 2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O 2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline PO 2 in both the cortex and medulla. SGLT inhibition improved cortical PO 2 in the diabetic kidney, whereas it reduced medullary PO 2 in both groups. SGLT inhibition reduced Na ϩ transport efficiency [tubular Na ϩ transport (TNa)/renal O2 consumption (QO2)] in the control kidney, whereas the already reduced TNa/QO 2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex PO 2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary PO 2 in both control and diabetic kidneys during the inhibition of proximal Na ϩ reabsorption suggests the redistribution of active Na ϩ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia. diabetes; oxgen consumption; renal hypoxia; sodium-glucose linked transport; sodium transport DIABETES affects up to 220 million people worldwide (15). Diabetic nephropathy is a renal complication of type 1 and type 2 diabetes and is a major cause of morbidity and mortality affecting up to 40% of diabetic patients (9). More recently, Na ϩ -glucose linked transport (SGLT) inhibition has become a frontline pharmacological target in the treatment of diabetes because of its ability to lower blood glucose levels by promoting the excretion of glucose by the kidney.Indeed, in a healthy kidney, 99% of filtered glucose is reabsorbed, mostly via high-capacity SGLT2, which is expressed in the brush-border membrane of the proximal tubule in the S1 segment (39), and, to a lesser extent, via low-capacity SGLT1, which is expressed in the S3 segment of the proximal tubule (2). Glucose is transported out of proximal tubules and into the surrounding interstitium via glucose transporter 2. The reabsorption of glucose ...

O'Neill J, Corbett A, Johns EJ. Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1-7) administration in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 304: R260 -R266, 2013. First published December 19, 2012 doi:10.1152/ajpregu.00583.2011-Angiotensin II at the kidney regulates renal hemodynamic and excretory function, but the actions of an alternative metabolite, angiotensin (1-7), are less clear. This study investigated how manipulation of dietary sodium intake influenced the renal hemodynamic and excretory responses to intrarenal administration of angiotensin (1-7). Renal interstitial infusion of angiotensin (1-7) in anesthetized rats fed a normal salt intake had minimal effects on glomerular filtration rate but caused dose-related increases in urine flow and absolute and fractional sodium excretions ranging from 150 to 200%. In rats maintained for 2 wk on a low-sodium diet angiotensin (1-7) increased glomerular filtration rate by some 45%, but the diuretic and natriuretic responses were enhanced compared with those in rats on a normal sodium intake. By contrast, renal interstitial infusion of angiotensin (1-7) in rats maintained on a high-sodium intake had no effect on glomerular filtration rate, whereas the diuresis and natriuresis was markedly attenuated compared with those in rats fed either a normal or low-sodium diet. Plasma renin and angiotensin (1-7) were highest in the rats on the low-sodium diet and depressed in the rats on a high-sodium diet. These findings demonstrate that the renal hemodynamic and excretory responses to locally administered angiotensin (1-7) is dependent on the level of sodium intake and indirectly on the degree of activation of the renin-angiotensin system. The exact way in which angiotensin (1-7) exerts its effects may be dependent on the prevailing levels of angiotensin II and its receptor expression.angiotensin (1-7); dietary sodium; renal hemodynamics; sodium excretion THE RENIN ANGIOTENSIN SYSTEM (RAS) is a powerful endogenous hormonal cascade that plays a central role in the regulation of blood pressure, sodium balance, and body fluid homeostasis. Classically, this cascade culminates in the formation of the potent vasoconstrictor, antinatriuretic and antidiuretic peptide angiotensin II (ANG II) (7,20). ANG II is produced from angiotensin I (ANG I) primarily via angiotensin-converting enzyme (ACE) but also via the tissue enzyme chymase. The latter has been shown to contribute to the production of ANG II in the diabetic mouse kidney (21). More recently, another RAS peptide called angiotensin (1-7) [ANG (1-7)] has been described as the endogenous counter regulator of ANG II (16) via activation of its "mas" receptor (24). ANG (1-7) is formed directly from ANG II by the ACE isoform ACE 2 (27, 32) but can also be synthesized directly from ANG I via tissue-specific peptidases such as neprilysin in the kidney (2).The intrarenal actions of ANG (1-7) and its interaction with ANG II on renal hemodynamics and tubular fluid reabsorption h...

Chronic kidney disease (CKD) occurs in more than 50% of patients with obstructive sleep apnea (OSA). However, the impact of intermittent hypoxia (IH) on renal function and oxygen homeostasis is unclear. Male Sprague-Dawley rats were exposed to IH (270 s at 21% O2; 90 s hypoxia, 6.5% O2 at nadir) for 4 h [acute IH (AIH)] or to chronic IH (CIH) for 8 h/day for 2 wk. Animals were anesthetized and surgically prepared for the measurement of mean arterial pressure (MAP), and left renal excretory function, renal blood flow (RBF), and renal oxygen tension (Po2). AIH had no effect on MAP (123 ± 14 vs. 129 ± 14 mmHg, means ± SE, sham vs. IH). The CIH group was hypertensive (122 ± 9 vs. 144 ± 15 mmHg, P < 0.05). Glomerular filtration rate (GFR) (0.92 ± 0.27 vs. 1.33 ± 0.33 ml/min), RBF (3.8 ± 1.5 vs. 7.2 ± 2.4 ml/min), and transported sodium (TNa) (132 ± 39 vs. 201 ± 47 μmol/min) were increased in the AIH group (all P < 0.05). In the CIH group, GFR (1.25 ± 0.28 vs. 0.86 ± 0.28 ml/min, P < 0.05) and TNa (160 ± 39 vs. 120 ± 40 μmol/min, P < 0.05) were decreased, while RBF (4.13 ± 1.5 vs. 3.08 ± 1.5 ml/min) was not significantly different. Oxygen consumption (QO2) was increased in the AIH group (6.76 ± 2.60 vs. 13.60 ± 7.77 μmol/min, P < 0.05), but it was not significantly altered in the CIH group (3.97 ± 2.63 vs. 6.82 ± 3.29 μmol/min). Cortical Po2 was not significantly different in the AIH group (46 ± 4 vs. 46 ± 3 mmHg), but it was decreased in the CIH group (44 ± 5 mmHg vs. 38 ± 2 mmHg, P < 0.05). For AIH, renal oxygen homeostasis was preserved through a maintained balance between O2 supply (RBF) and consumption (GFR). For CIH, mismatched TNa and QO2 reflect inefficient O2 utilization and, thereby, sustained decrease in cortical Po2.

Background: Under normal physiological conditions, renal tissue oxygen is tightly regulated. At high altitude, a physiological challenge is imposed by the decrease in atmospheric oxygen. At the level of the kidney, the physiological adaptation to high altitude is poorly understood, which might relate to different integrated responses to hypoxia over different time domains of exposure. Thus, this systematic review sought to examine the renal physiological adaptation to high altitude in the context of the magnitude and duration of exposure to high altitude in the healthy kidney model. Methods: To conduct the review, three electronic databases were examined: OVID, PubMed, and Scopus. Search terms included: Altitude, renal, and kidney. The broad, but comprehensive search, retrieved 1,057 articles published between 1997 and April 2020. Fourteen studies were included in the review. Results: The inconsistent effect of high altitude on renal hemodynamic parameters (glomerular filtration rate, renal blood flow, and renal plasma flow), electrolyte balance, and renal tissue oxygen is difficult to interpret; however, the data suggest that the nature and extent of renal physiological adaptation at high altitude appears to be related to the magnitude and duration of the exposure. Conclusion: It is clear that renal physiological adaptation to high altitude is a complex process that is not yet fully understood. Further research is needed to better understand the renal physiological adaptation to hypoxia and how renal oxygen homeostasis and metabolism is defended during exposure to high altitude and affected as a long-term consequence of renal adaptation at high altitude.

What is the central question of this study? Dietary sodium manipulation alters the magnitude of angiotensin-(1-7) [Ang-(1-7)]-induced natriuresis. The present study sought to determine whether this was related to relative changes in the activity of intrarenal Mas and/or AT receptors. What is the main finding and its importance? Angiotensin-(1-7)-induced diuresis and natriuresis is mediated by intrarenal Mas receptors. However, intrarenal AT receptor blockade also had an inhibitory effect on Ang-(1-7)-induced natriuresis and diuresis. Thus, Ang-(1-7)-induced increases in sodium and water excretion are dependent upon functional Mas and AT receptors. We investigated whether angiotensin-(1-7) [Ang-(1-7)]-induced renal haemodynamic and excretory actions were solely dependent upon intrarenal Mas receptor activation or required functional angiotensin II type 1 (AT ) receptors. The renin-angiotensin system was enhanced in anaesthetized rats by prior manipulation of dietary sodium intake. Angiotensin-(1-7) and AT and Mas receptor antagonists were infused into the kidney at the corticomedullary border. Mas receptor expression was measured in the kidney. Mean arterial pressure, urine flow and fractional sodium excretion were 93 ± 4 mmHg, 46.1 ± 15.7 μl min kg and 1.4 ± 0.3%, respectively, in the normal-sodium group and 91 ± 2 mmHg, 19.1 ± 3.3 μl min kg and 0.7 ± 0.2%, respectively, in the low-sodium group. Angiotensin-(1-7) infusion had no effect on mean arterial pressure in rats receiving a normal-sodium diet but decreased it by 4 ± 5% in rats receiving a low-sodium diet (P < 0.05). Interstitial Ang-(1-7) infusion increased urine flow twofold and fractional sodium excretion threefold (P < 0.05) in rats receiving a normal-sodium diet and to a greater extent, approximately three- and fourfold, respectively, in rats receiving the low-sodium diet (both P < 0.05). Angiotensin-(1-7)-induced increases in urine flow and fractional sodium excretion were absent in both dietary groups during intrarenal AT or Mas receptor inhibition after either losartan or A-779, respectively. Thus, AT receptor activation, as well as Mas receptor activation, plays an essential role in mediating Ang-(1-7)-induced natriuresis and diuresis. Whether this is because Ang-(1-7) partly antagonizes AT receptors or whether Ang-(1-7)-induced natriuresis is mediated through AT -Mas receptor dimerization remains unclear.