Evaluation of Renal Hypoxia in Diabetic Mice by BOLD MRI

Abstract

Objective Renal hypoxia has been proposed to be a pathophysiologic feature of diabetic kidney disease but it has been difficult to demonstrate in vivo, particularly in mouse models of diabetes. The objective of this work was to examine the sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to assess renal oxygenation in vivo in a mouse model of diabetic kidney disease, the db/db mice. Research Design and Methods Kidney BOLD MRI studies were performed on a 3.0 T scanner using multiple gradient echo sequence with a custom-designed surface coil to acquire T2*-weighted images. Studies were performed in 10-week-old db/db mice (n = 7) and db/m controls (n = 6). Results R2* is a measure of the tissue deoxyhemoglobin concentration and higher values of R2* are associated with hypoxia. The db/db mice had higher medullary (43.1 ± 5.1 s−1 vs. 32.3 ± 3.7 s−1, P = 0.001) and cortical R2* (31.7 ± 3.1 s−1 vs. 27.1 ± 4.1 s−1, P = 0.04) values. Using pimonidazole staining as a marker of kidney hypoxia, in kidney sections from 10-week-old db/db mice neither cortex nor medulla had significant differences as compared with 10-week-old db/m mice (cortex: db/db 2.14 ± 0.05 vs. db/m 2.02 ± 0.28, medulla: db/db 2.81 ± 0.08 vs. db/m 2.6 ± 0.08). The db/db mice demonstrated further increased cortical and medullary hypoxia when scanned again at 15 weeks of age. Conclusions The report shows that renal BOLD MRI is a sensitive method for the in vivo evaluation of renal hypoxia in a mouse model of diabetic kidney disease where progressive renal hypoxia can be documented over time. BOLD MRI may be useful to monitor therapeutic interventions that may improve tissue hypoxia in the diabetic kidney.

Blood oxygenation level-dependent MRI for assessment of renal oxygenation

“…11,24,25 In humans with early type 1 diabetic nephropathy with proteinuria studied by BOLD MRI, furosemide also increased cortical and medullary oxygenation. 26 Pruijm et al 27 studied the response to furosemide in healthy controls (n=45), subjects with CKD (n=95), and treated hypertensive subjects with well-preserved renal function (n=58).…”

“…2,11,[24][25][26]40,[46][47][48][49][50] With few exceptions, renal hypoxia has been demonstrated by BOLD MRI in experimental models of diabetes mellitus, including streptozotocin-induced diabetes in the rat, Cohen diabetic rats, and db/db mice. 2,11,24,25,48 Of note, Peng et al 24 also found increased fat content in kidneys from db/db mice, which may have contributed to the observed reduction in T2* attributed to hypoxia. Five days after induction of diabetes mellitus in rats with streptozotocin, Ries et al 11 utilized BOLD MRI to demonstrate hypoxia in all regions of the kidney, in particular in the outer stripe of the outer medulla.…”

“…In this regard, furosemide reverses renal hypoxia in experimental diabetes, presumably by decreasing tubular sodium transport and oxygen consumption. 11,24,25 However, causation is more complex, since renal tissue hypoxia has been dissociated from hyperfiltration in experimental models of diabetes mellitus. 51 Experimental diabetes mellitus is also associated with mitochondrial dysfunction and reduced efficiency of oxygen utilization due to enhanced generation of reactive oxygen species, increased angiotensin II levels, and reduced nitric oxide availability.…”

Methods of Blood Oxygen Level-Dependent Magnetic Resonance Imaging Analysis for Evaluating Renal Oxygenation

“…Over the last two decades, BOLD MRI has been widely used to assess changes in renal oxygen level in various kidney disease conditions, for instance, ischemic [18], hypertensive [19], diabetic [20-23] and contrast [24-26] nephropathies as well as nephrotic syndrome [27], lupus nephritis [28, 29], chronic kidney disease [30-32], acute kidney injury [33, 34] and renal allograft rejection [35-39]. It is interesting to note that BOLD MRI studies with many analytical methods in patients with different etiologies have shown inconsistent and contradictory results, reporting higher or lower R2* values.…”

Comparative Effect of a Renin Inhibitor and a Thiazide Diuretic on Renal Tissue Oxygenation in Hypertensive Patients

“…Hence several hypotheses linking hypoxia-induced renal lesions with hypertension or renal diseases progression could not be verified in humans. Nowadays, blood oxygenation-level dependent MRI (BOLD-MRI) enables a non-invasive assessment of renal tissue oxygenation in animals and humans, high R2* values corresponding to low tissue oxygenation [10][11][12][13][14][15][16][17]. With this new approach several studies have been conducted in patients with hypertension and/or CKD and so far discrepant results have been reported [18].…”