Abstract
Patients with diabetic hypertensive nephropathy have accelerated disease progression. Diabetes and hypertension have both been associated with changes in renal catecholamines and reactive oxygen species. With a specific focus on renal catecholamines and oxidative stress we examined a combined model of hypertension and diabetes using normotensive BPN/3J and hypertensive BPH/2J Schlager mice. Induction of diabetes (5 × 55 mg/kg streptozotocin i.p.) did not change the hypertensive status of BPH/2J mice (telemetric 24 h avg. MAP, non-diabetic 131 ± 2 vs. diabetic 129 ± 1 mmHg, n.s at 9 weeks of study). Diabetes-associated albuminuria was higher in BPH/2J vs. diabetic BPN/3J (1205 + 196/-169 versus 496 + 67/-59 μg/24 h, p = 0.008). HPLC measurement of renal cortical norepinephrine and dopamine showed significantly greater levels in hypertensive mice whilst diabetes was associated with significantly lower catecholamine levels. Diabetic BPH/2J also had greater renal catecholamine levels than diabetic BPN/3J (diabetic: norepinephrine BPN/3J 40 ± 4, BPH/2J 91 ± 5, p = 0.010; dopamine: BPN/3J 2 ± 1; BPH/2J 3 ± 1 ng/mg total protein, p < 0.001 after 10 weeks of study). Diabetic BPH/2J showed greater cortical tubular immunostaining for monoamine oxidase A and cortical mitochondrial hydrogen peroxide formation was greater in both diabetic and non-diabetic BPH/2J. While cytosolic catalase activity was greater in non-diabetic BPH/2J it was significantly lower in diabetic BPH/2J (cytosolic: BPH/2J 127 ± 12 vs. 63 ± 6 nmol/min/ml, p < 0.001). We conclude that greater levels of renal norepinephrine and dopamine associated with hypertension, together with diabetes-associated compromised anti-oxidant systems, contribute to increased renal oxidative stress in diabetes and hypertension. Elevations in renal cortical catecholamines and reactive oxygen species have important therapeutic implications for hypertensive diabetic patients.
Highlights
Diabetic patients often have concomitant conditions such as hypertension with such patients having a greatly accelerated development of nephropathy (Bakris et al, 2000)
Diabetes was associated with significantly lower body weight as well as increases in water intake and urine output (Table 1) while non-diabetic control hypertensive animals were lighter than normotensive mice
We found that insulin-deficient diabetes was associated with significantly lower levels of renal dopamine and norepinephrine while hypertension was associated with significantly greater levels of these catecholamines
Summary
Diabetic patients often have concomitant conditions such as hypertension with such patients having a greatly accelerated development of nephropathy (Bakris et al, 2000). The neural catecholamine, norepinephrine, modulates glomerular filtration rate directly, as well as influencing release of humoral effectors including renin and prostaglandin. Via noradrenaline can directly increase renal tubular sodium reabsorption (Berne et al, 1952;Johns et al, 2011). Noradrenaline induces increases of sodiumglucose cotransporter 2 and the glucose transporter GLUT2 gene expression in HK2 cells in vitro (Rafiq et al, 2015) while renal denervation decreased protein levels of GLUT2 in diabetic and non-diabetic rat kidney cortex (Schaan et al, 2005). In the kidney the catecholamine dopamine is predominantly produced by renal tubules where it too stimulates renin release and can cause natriuresis, as well as inhibiting tubuloglomerular feedback (for review see Zhang et al, 2009; Armando et al, 2011)
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