Renal dopaminergic system dysfunction and its association with arterial hypertension and renal inflammation in an experimental model of metabolic syndrome induced by fructose overload

RUKAVINA MIKUSIC NL; KOUYOUMDZIAN NM; KRAVETZ MC; DEL MAURO J; LEE HJ; PUYÓ AM; GIRONACCI MM; TOBLLI JE; FERNÁNDEZ BE; CHOI MR

Ciudad Autónoma de Buenos Aires

Congreso; III International Congress in Translational Medicine; 2016

Sociedad Argentina de Investigación Clínica (SAIC)

Introduction: Renaldopaminergic system (RDS) is a local natriuretic system that regulates renalfunction and blood pressure levels through inhibition of sodium transporters attubular level, being the most important the enzyme Na+, K+-ATPase (NKA). A high fructose diet induces metabolic and hemodynamic changesthat could be associated with an impairment of the RDS, leading to sodiumretention, arterial hypertension and renal dysfunction. Aim: The aim ofthe study was to evaluate RDS state and its association with the development ofhypertension, overexpression and activity of renal NKA and the presence ofglomerular damage markers (nephrin and microalbuminuria) in fructose overloaded(FO) rats. Methods: Male Sprague Dawley rats were assigned to Control (C, tap water) or FO(10% w/v of fructose solution) groups, during 4, 8 and 12 weeks (n=8/group/period).Systolic blood pressure (SBP), metabolic parameters, and urinary L-dopa and dopamine(DA), creatinine, sodium and albumin were measured. 24-hour diuresis and urinary sodium excretion were determined.NKA activity wasassessed by Fiske-Subarrow method and its expression was measured by western blot andimmunofluorescence. Western blot analysis of renal expression of D1 receptor (D1R) andnephrin was also performed.  Results:FO increased SBP (mmHg, C4: 121±8 vs. F4: 145±1*; C8: 130±4 vs. F8: 161±10#;C12: 133±5 vs. F12: 163±4#), which positively correlated (R2=0.78; p<0.002)to corresponding urinary L-dopa/DA index at same period time (C4: 0.49±0.05 vs.F4: 1.9±0.09#; C8: 0.53±0.06 vs. F8: 2.35±0.1#; C12: 0.54±0.07 vs. F12:2.57±0.2#). FO also reduced urinary sodium excretion (mEq/24 hs, C4: 1.01±0.05vs F4: 0.83±0.04*; C8: 1.02±0.08 vs F8: 0.72±0.05#; C12: 1.04±0.08 vs F12:0.64±0.04#). These changes were accompanied by an increase in renal NKAspecific activity (nmol/mg/min, C4: 120±12 vs F4: 172±16*; C8: 124±16 vs F8:186±17*; C12: 140±18 vs F12: 223±21#) an in its expression evidenced by westernblot (C4: 1.00±0.03 vs F4: 1.54±0.02#; C8: 1.00±0.02 vs F8: 1.39±0.07#; C12:1.00±0.02 vs F12: 1.24±0.10*) and immunofluorescence. A decrease in renal D1Rexpression (C4: 1 .00 ± 0.05 vs. F4: 0.7 2 ± 0.08*; C8: 1 .00 ± 0.05 vs. F8:0.7 5 ±0.07 *) was found. Microalbuminuria (C12:13.11±1.4 vs F12:57.6±2.5#) anda significant decrease in nephrin expression (C12: 1.00±0.10 vs. F12: 0.73±0.05#)were only observed at week 12. (*p<0.05, #p<0.01 vs. C). Conclusion:FO was associated with an increased L-dopa/DA index and decreased D1R expressionsince week 4 of treatment. The RDS dysfunction was accompanied by an increase inblood pressure levels and renal expression and activity of NKA in allexperimental periods. Alteration of L-dopa/DA index could be postulated as an earliermarker of renal dysfunction, easy to detect before structural damage were evidencedby other markers such as microalbuminuria and decreased nephrin expression.