Effects of chronic fructose overload on renal dopaminergic system: alteration of urinary L-dopa/dopamine index correlates to hypertension and precedes kidney structural damage

Abstract

Insulin resistance induced by a high-fructose diet has been associated to hypertension and renal damage. The aim of this work was to assess alterations in the urinary L-dopa/dopamine ratio over three time periods in rats with insulin resistance induced by fructose overload and its correlation with blood pressure levels and the presence of microalbuminuria and reduced nephrin expression as markers of renal structural damage. Male Sprague-Dawley rats were randomly divided into six groups: control (C) (C4, C8 and C12) with tap water to drink and fructose-overloaded (FO) rats (FO4, FO8 and FO12) with a fructose solution (10% w/v) to drink for 4, 8 and 12 weeks. A significant increase of the urinary L-dopa/dopamine ratio was found in FO rats since week 4, which positively correlated to the development of hypertension and preceded in time the onset of microalbuminuria and reduced nephrin expression observed on week 12 of treatment. The alteration of this ratio was associated to an impairment of the renal dopaminergic system, evidenced by a reduction in renal dopamine transporters and dopamine D1 receptor expression, leading to an overexpression and overactivation of the enzyme Na, K-ATPase with sodium retention. In conclusion, urinary L-dopa/dopamine ratio alteration in rats with fructose overload positively correlated to the development of hypertension and preceded in time the onset of renal structural damage. This is the first study to propose the use of the urinary L-dopa/dopamine index as marker of renal dysfunction that temporarily precedes kidney structural damage induced by fructose overload.

Losartan prevents the imbalance between renal dopaminergic and renin angiotensin systems induced by fructose overload. l-Dopa/dopamine index as new potential biomarker of renal dysfunction

“…Taking into account the complex opposing and counter-regulatory interaction between RAS and RDS at renal level, it can be proposed that one of the effects of AT 1 R over-expression and Ang II increased levels would be a reduction of DA production. Supporting this hypothesis, F rats showed an increased urinary L-dopa/DA ratio since week 4, due to a reduction in DA urinary excretion accompanied by an increase in L-dopa urinary excretion, as we have previously reported [27]. In vitro studies from our group have proven that Ang II is able to reduce DA tubular uptake, a process mediated by members of the SLC22A family called OCTs [28].…”

Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets

“…However, there is the caveat that these much greater amounts of fructose also cause metabolic syndrome, insulin resistance and increase plasma triglycerides [ 61 ]. Additionally, lower amounts of fructose cause hypertension over longer time frames of 8–12 weeks [ 62 , 63 ]. Taken together these results lead us to propose that the blood pressure effects of fructose are proportional to the amount of fructose, salt content of the diet, and time, such that when fructose makes up a high percentage of caloric intake it increases blood pressure in a short period of time even when animals are on normal salt.…”

Cardiotoxic Effects of the Antineoplastic Doxorubicin in a Model of Metabolic Syndrome: Oxidative Stress and Transporter Expression in the Heart

“…In agreement with other reports, this study shows that an F-rich diet increased blood pressure, plasma triglyceride levels, and water intake and decreased food intake. 34,41–43 The absence of body weight gain in animals with F overload has been reported in various experimental works. 34,41 The absence of differences in body weight levels between control and F-overloaded rats could be associated with unchanged caloric intake, which in turn could be due to higher F intake accompanied by a reduction in food intake.…”

“…In agreement with other reports, this study shows that an F-rich diet increased blood pressure, plasma triglyceride levels, and water intake and decreased food intake. 34,[41][42][43] The absence of body weight gain in animals with F overload has been reported in various experimental works. 34,41 The absence of differences in body weight levels between control and F-overloaded rats could be associated with unchanged caloric intake, which in turn could be due to higher F intake accompanied by a reduction in food intake.…”

“…Finally, the pellets were resuspended with 200 μL of lysis buffer as previously described. 34 Samples of left ventricle containing similar amounts of protein (100 μg protein/lane) were separated by electrophoresis in 8% sodium dodecyl sulfate polyacrylamide gels (Bio-Rad Labs Inc, Hercules, CA) and then transferred into nitrocellulose membranes (Bio-Rad, Munich, Germany). Nonspecific binding was blocked by incubation with 3% non-fat dry milk in 10 mM PBS (pH 7.40) and 0.1% Tween 20 for 1 hour at room temperature.…”