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Oxygen tension in the kidney is mostly determined by O 2 consumption (Qo 2 ), which is, in turn, closely linked to tubular Na + reabsorption. The objective of the present study was to develop a model of mitochondrial function in the proximal tubule (PT) cells of the rat renal cortex to gain more insight into the coupling between Qo 2 , ATP formation (G ATP ), ATP hydrolysis (Q ATP ), and Na + transport in the PT. The present model correctly predicts in vitro and in vivo measurements of Qo 2 , G ATP , and ATP and P i concentrations in PT cells. Our simulations suggest that O 2 levels are not rate limiting in the proximal convoluted tubule, absent large metabolic perturbations. The model predicts that the rate of ATP hydrolysis and cytoplasmic pH each substantially regulate the G ATP -to-Qo 2 ratio, a key determinant of the number of Na + moles actively reabsorbed per mole of O 2 consumed. An isolated increase in Q ATP or in cytoplasmic pH raises the G ATP -to-Qo 2 ratio. Thus, variations in Na + reabsorption and pH along the PT may, per se, generate axial heterogeneities in the efficiency of mitochondrial metabolism and Na + transport. Our results also indicate that the G ATP -to-Qo 2 ratio is strongly impacted not only by H + leak permeability, which reflects mitochondrial uncoupling, but also by K + leak pathways. Simulations suggest that the negative impact of increased uncoupling in the diabetic kidney on mitochondrial metabolic efficiency is partly counterbalanced by increased rates of Na + transport and ATP consumption. This model provides a framework to investigate the role of mitochondrial dysfunction in acute and chronic renal diseases.

Aim: Common kidney alterations early after the onset of insulinopenic diabetes include glomerular hyperfiltration, increased oxygen consumption and tissue hypoxia. Increased activity of the renin-angiotensin-aldosterone system (RAAS) has been implicated in most of these early alterations. The RAAS peptide angiotensin (1-7) has the potential to modulate RAAS-mediated alterations in kidney function. Thus, the aim of the present study was to determine the acute effects of angiotensin (1-7) in the kidney of insulinopenic type 1 diabetic rat and the results compared to that of normoglycaemic controls., Methods: Renal haemodynamics and oxygen homeostasis were measured 3 weeks after administration of streptozotocin before and after acute intrarenal infusion of angiotensin (1-7) at a dose of 400 ng min -1 ., Results: Arterial pressure and renal blood flow were similar between groups and not affected by exogenous angiotensin (1-7). Diabetics presented with glomerular hyperfiltration, increased urinary sodium excretion and elevated kidney oxygen consumption. Angiotensin (1-7) infusion normalized glomerular filtration, increased urinary sodium excretion, decreased proximal tubular reabsorption, and elevated kidney oxygen consumption even further. The latter resulting in tubular electrolyte transport inefficiency. Angiotensin (1-7) did not affect tissue oxygen tension and had no significant effects in controls on any of the measured parameters., Conclusion: Diabetes results in increased responsiveness to elevated levels of angiotensin (1-7) which is manifested as inhibition of tubular sodium transport and normalization of glomerular filtration. Furthermore, elevated angiotensin (1-7) levels increase kidney oxygen consumption in the diabetic kidney even further which affects tubular electrolyte transport efficiency negatively., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO2) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin-diabetic rats. Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO2 was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase. Results Both CM reduced QO2 in human PTC (about -35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO2 (-34%). Both CM decreased QO2 in PTC from diabetic rats (-38% and -36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC. Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO2. Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy.

Aims/hypothesis: Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown., Methods: The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes., Results: Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals., Conclusions/interpretation: Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na(+)-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 Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 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 Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na(+) transport efficiency [tubular Na(+) transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 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 Po2 in both control and diabetic kidneys during the inhibition of proximal Na(+) reabsorption suggests the redistribution of active Na(+) transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia., (Copyright © 2015 the American Physiological Society.)

The kidneys account for about 10% of the whole body oxygen consumption, whereas only 0.5% of the total body mass. It is known that intrarenal hypoxia is present in several diseases associated with development of kidney disease, including diabetes, and when renal blood flow is unaffected. The importance of deranged oxygen metabolism is further supported by deterioration of kidney function in patients with diabetes living at high altitude. Thus, we argue that reduced oxygen availability alters renal energy metabolism. Here, we introduce a novel magnetic resonance imaging (MRI) approach to monitor metabolic changes associated with diabetes and oxygen availability. Streptozotocin diabetic and control rats were given reduced, normal, or increased inspired oxygen in order to alter tissue oxygenation. The effects on kidney oxygen metabolism were studied using hyperpolarized [1-(13)C]pyruvate MRI. Reduced inspired oxygen did not alter renal metabolism in the control group. Reduced oxygen availability in the diabetic kidney altered energy metabolism by increasing lactate and alanine formation by 23% and 34%, respectively, whereas the bicarbonate flux was unchanged. Thus, the increased prevalence and severity of nephropathy in patients with diabetes at high altitudes may originate from the increased sensitivity toward inspired oxygen. This increased lactate production shifts the metabolic routs toward hypoxic pathways.

Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO₂). We investigated the effect of Ang II on QO₂ in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H₂O₂ for 48 h. QO₂ was determined during baseline (113 mmol/l NaCl; transport-dependent QO₂) and during sodium-free conditions (transport-independent QO₂). Ang II reduced transport-dependent QO₂ in wild-types, but not in p22(phox) which also displayed increased QO₂ at baseline. Transport-independent QO₂ was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO₂ in wild-type. Addition of H₂O₂ reduced transport-dependent QO₂ in wild-types, but not in p22(phox). Transport-independent QO₂ was unaffected by H₂O₂. The similar effects of Ang II and H₂O₂ to reduce transport-dependent QO₂ suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO₂ was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO₂ was not replicated by H₂O₂, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO₂ in proximal tubular cells and may be an important pathway modulating renal QO₂.

Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

The high renal oxygen (O(2) ) demand is associated primarily with tubular O(2) consumption (Qo(2) ) necessary for solute reabsorption. Increasing O(2) delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension. The metabolic efficiency for solute transport (Qo(2) /T(Na) ) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na(+) transporters, different levels of oxidative stress and segmental tubular dysfunction. Sustained hyperglycaemia results in increased kidney Qo(2) , partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased Qo(2) is not matched by a similar increase in O(2) delivery. Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O(2) cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function. Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O(2) metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice., (© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.)

Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria, and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by ANG II that limits oxygen delivery and increases oxidative stress, resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport, and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of ANG II activity, by either blocking ANG II type 1 receptors or angiotensin-converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. Therefore, it seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage, and perhaps also persistence the high blood pressure.

In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.

Background: Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats., Methods: Oxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot., Results: Proximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin + SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47(phox) and nNOS and the treatments prevented these increases., Conclusions: Diabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (Q(O(2)). Diabetic kidneys have reduced NO availability and increased Q(O(2)). However, the exact nitric oxide synthase (NOS) isoform regulating Q(O(2)), hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na(+) transport (T(Na))/Q(O(2))], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-L-thiocitrulline (SMTC) or the nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Diabetic rats had higher baseline Q(O(2)) and GFR than control rats, although RBF was similar in the groups. SMTC and L-NAME increased Q(O(2)) and reduced T(Na)/Q(O(2)) only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by L-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in L-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased Qo(2) and reduced T(Na)/Q(O(2)) in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of Q(O(2)) and tissue oxygenation in these kidneys.

Purpose of Review: The regulatory role of nitric oxide for tissue oxygen availability involves both oxygen delivery, through regulation of vascular tone, and oxygen consumption, through interference with mitochondrial respiration and tubular transport capacity. This review highlights recent findings regarding mechanisms of dysfunctional nitric oxide bioavailability in the kidney and the implications for oxygen availability and mitochondrial respiration., Recent Findings: It has been revealed that nitric oxide has several ways to influence and regulate kidney function during normal physiological conditions and that it is also involved in many of the mechanisms resulting in altered kidney function during disease. Recent reports show that nitric oxide regulates kidney oxygenation by influencing both oxygen utilization and supply., Summary: Increasing evidence has accumulated during recent years for a dysfunctional nitric oxide system resulting in altered kidney oxygenation in several pathological conditions, which contributes to the development of kidney failure. We presently have extensive knowledge regarding the interplay between nitric oxide, oxygenation and kidney function; however, more effort is needed to clarify how dysfunctional nitric oxide regulation progresses to tissue hypoxia and kidney failure in various conditions, in order to identify potential therapeutic targets and develop strategies to prevent or alleviate these adverse effects and maintain adequate kidney function.

Diabetic nephropathy is a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function remains unclear, although several hypotheses have been postulated. The cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through the polyol pathway and formation of advanced glycation end-products. The renal effects in vivo of each and every one of these mechanisms are even less clear. However, there is growing evidence that hyperglycaemia results in altered renal oxygen metabolism and decreased renal oxygen tension and that these changes are linked to altered kidney function. Clinical data regarding renal oxygen metabolism and oxygen tension are currently rudimentary and our present understanding regarding renal oxygenation during diabetes is predominantly derived from data obtained from animal models of experimental diabetic nephropathy. This review will present recent findings regarding the link between hyperglycaemia and diabetes-induced alterations in renal oxygen metabolism and renal oxygen availability. A possible link between reduced renal oxygen tension and the development of diabetic nephropathy includes increased polyol pathway activity and oxidative stress, which result in decreased renal oxygenation and subsequent activation of hypoxia-inducible factors. This initiates increased gene expression of numerous genes known to be involved in development of diabetic nephropathy.

During conditions with experimental diabetes mellitus, it is evident that several alterations in renal oxygen metabolism occur, including increased mitochondrial respiration and increased lactate accumulation in the renal tissue. Consequently, these alterations will contribute to decrease the interstitial pO2, preferentially in the renal medulla of animals with sustained long-term hyperglycemia.

Purpose: To evaluate controversial results regarding the effect of the contrast medium (CM) iothalamate on renal medullary blood flow by applying two different methods simultaneously., Material and Methods: The outer medullary blood flow (OMBF) response was estimated using laser-Doppler flowmetry and hydrogen gas wash-out (microelectrodes) simultaneously. Outer medullary oxygen tension (PO2) was measured using Clark type microelectrodes. Iothalamate was injected i.v. at 1600 mg I/kg body weight for 2 min., Results: CM induced a transient 28% decrease in OMBF as measured with the laser Doppler. The hydrogen gas wash-out rate was reduced by 50%, indicating a reduced perfusion. CM induced a transient 60% reduction in PO2, while renal fluid and electrolyte excretion increased several fold., Conclusion: The CM iothalamate reduces outer medullary perfusion as estimated by two different techniques applied simultaneously. The PO2 in the same region was also reduced. Previous controversies regarding the effect of iothalamate on OMBF can be explained by extreme dosage and injection rates greatly exceeding clinical relevance.

Abstract: Aim: Uncoupling protein‐2 (UCP‐2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP‐2−/− mice, we tested the hypothesis that UCP‐2‐mediated leak respiration is important for the development of diabetes‐induced intrarenal hypoxia and proteinuria. Methods: Kidney function, in vivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild‐type and UCP‐2−/− mice during normoglycaemia and 2 weeks after diabetes induction. Results: Diabetic wild‐type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM‐1 excretion. However, diabetic UCP‐2−/− mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM‐1 excretion. Conclusion: Although functioning as an antioxidant system, mitochondria uncoupling is always in co‐occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP‐2‐mediated mitochondrial leak respiration is necessary for the development of diabetes‐induced intrarenal tissue hypoxia and proteinuria. [ABSTRACT FROM AUTHOR]