The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

Abstract

OBJECTIVE-Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).RESEARCH DESIGN AND METHODS-Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR Ն135 ml/min per 1.73 m 2 ), and 12 subjects exhibited normofiltration (GFR Ͻ135 ml/min per 1.73 m 2 ).RESULTS-Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 Ϯ 5 to 139 Ϯ 5 ml/min per 1.73 m 2 ) but increased GFR in the normofiltration group (118 Ϯ 5 to 138 Ϯ 5 ml/min per 1.73 m 2 ). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.CONCLUSIONS-In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states. Diabetes 57: 688-695, 2008 A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3-5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.Animal studies have examined the role of vasodilatation (7) in the pathogenesis of hyperfiltration. Early work focused on the role of cyclooxygenase (COX)-derived prostanoids, which exert a variety of functions in the kidney, including important vasodilatory effects; however, studies initially used nonspecific COX1/COX2 inhibitors (8). With the discovery of the COX2 isoform and selective COX2 inhibitors, experimental models of diabetes revealed that COX2 expression is increased in the macula densa in this condition and is associated with enhanced production of vasodilatory prostaglandins, RAS activation, and renal hyperfiltration (9). Moreover, in streptozotocininduced diabetic rat models with a renal hyperfiltration phenotype, hyperglycemia-associated prostaglandin production and hyperfiltration were blunted using COX2 inhibition (9). Given the association between renal hyperfiltration, intraglomerular hypertension, and nephropathy related to diabetes (7,10,11), the elucidation of COX2-mediated renal hemodynamic function changes in dia...

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

“…The highsodium diet was also used to avoid confounding effects of having inter-and intra-individual differences in sodium intake before and after direct renin inhibition (DRI), and to keep experimental conditions close to typical North American clinical conditions, in terms of diet. First, patients were studied after clamped euglycaemic (4-6 mmol/l) conditions had been maintained for approximately 6 h, a period of time previously demonstrated to be sufficient to influence vascular function and urinary cytokines/chemokines [8]. This level of ambient glycaemia was maintained during all investigations.…”

“…In all phases of the experiment, blood glucose was maintained by a modified glucose-clamp technique, as described previously [8]. In brief, a 16-gauge peripheral venous cannula was inserted into the left antecubital vein for infusion of glucose and insulin and a second cannula was inserted for blood sampling more distally.…”

“…HbA 1c was measured by high-performance liquid chromatography and plasma renin concentration and plasma insulin were measured using previously described methods [8,30].…”

“…GFR and effective renal plasma flow (ERPF) were estimated from steady-state infusion of inulin and PAH, respectively. Filtration fraction was derived as GFR/ERPF [8].…”

“…From a haemodynamic perspective in the kidney, the influence of hyperglycaemia manifests as a hyperfiltration response characterised by a rise in filtration fraction [2][3][4][5][6], which may cause renal injury through shear-stress effects [7][8][9]. The haemodynamic effects of hyperglycaemia are attributed, in part, to activation of the renin-angiotensin-aldosterone system (RAAS) [6].…”