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 ...

Aims/hypothesis Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. −1 ). UCP-2 protein levels were similar in untreated control and db/db mice (67± 9 vs 67± 4 optical density; OD) but were reduced in CoQ10 treated groups (43±2 and 38±7 OD). Conclusions/interpretation db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 mg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into b-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.

Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

Regulation of fluid balance is pivotal during surgery and anesthesia and affects patient morbidity, mortality, and hospital length of stay. Retention of sodium and water is known to occur during surgery but the mechanisms are poorly defined. In this study, we explore how the volatile anesthetic sevoflurane influences renal function by affecting renal sympathetic nerve activity (RSNA). Our results demonstrate that sevoflurane induces renal sodium and water retention during pediatric anesthesia in association with elevated plasma concentration of renin but not arginine–vasopressin. The mechanisms are further explored in conscious and anesthetized ewes where we show that RSNA is increased by sevoflurane compared with when conscious. This is accompanied by renal sodium and water retention and decreased renal blood flow (RBF). Finally, we demonstrate that renal denervation normalizes renal excretory function and improves RBF during sevoflurane anesthesia in sheep. Taken together, this study describes a novel role of the renal sympathetic nerves in regulating renal function and blood flow during sevoflurane anesthesia.