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 ...

Quantitative analyses of relevant molecules in faeces may have potential as future non-invasive measures of stress. This study examined levels of faecal corticosterone and immunoglubulin A (IgA) in young adult rats and how these levels varied according to age, gender and time of day. Faecal samples were collected from 40 young adult rats (7 weeks old, n = 20 and 10 weeks old, n = 20) of both sexes from two time windows: day and night. The concentrations of corticosterone and IgA were measured by ELISAs following organic solvent extraction and aqueous extraction, respectively, of the molecules from faecal pellets. The production of faeces per time unit was higher in males than in females, and linear correlations were found between the faecal concentrations of corticosterone and IgA and total amounts of the respective molecules excreted in faeces per kg body weight per hour. In all further analyses the levels of the two molecules were calculated as amounts secreted per kg of body weight per hour. There was no gender difference between females and males in the production of corticosterone and IgA, but 7-week-old animals excreted significantly higher amounts of both molecules than did 10-week-old rats. The levels of IgA excreted by female rats were higher in the evening than in the morning, and male rats excreted higher concentrations of corticosterone in the morning than in the evening.

The integrated response to hypotonic NaCl solutions (100, 50, 25, and 0 mM NaCl) in proximal duodenum of anesthetized rats was examined. Luminal alkalinization, fluid flux, duodenal contractions, blood-to-lumen clearance of 51Cr-labeled EDTA (mucosal permeability), and perfusate osmolality were studied in the absence and presence of the cyclooxygenase inhibitor indomethacin. In response to hypotonic solutions net fluid absorption, increases in permeability and perfusate osmolality were markedly higher in indomethacin-treated animals than in controls, and these effects were diminished by the nicotinic-receptor antagonist hexamethonium. Infusion of iloprost, a stable PGI2 analog, to indomethacin-treated animals markedly reduced the hypotonicity-induced increase in mucosal permeability and diminished the rise in perfusate osmolality. Lowering the NaCl concentration in the perfusion solution but maintaining isotonicity with mannitol had no effect on mucosal permeability. Very good linear correlations were obtained between the degree of luminal hypotonicity and the increase in permeability and between increases in permeability and perfusate osmolality. It is concluded that luminal hypotonicity increases duodenal mucosal permeability. The hypotonicity-induced increase in permeability modulated by prostaglandins and nicotinic receptors fulfills the function of increasing blood-to-lumen transport of Na+ facilitating adjustment of luminal osmolality.

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.

Luminal hypotonicity increases duodenal mucosal permeability by a neural mechanism involving 5-HT acting on 5-HT(3) and 5-HT(4) receptors. 5-HT also appears to participate in the regulation of the hypotonicity-induced fluid flux.