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

RUKAVINA MIKUSIC, NATALIA LUCÍA; KOUYOUMDZIAN, NICOLÁS MARTÍN; UCEDA, ANA; DEL MAURO, JULIETA SOFÍA; PANDOLFO, MARCELA; GIRONACCI, MARIELA MERCEDES; PUYÓ, ANA MARÍA; TOBLLI, JORGE EDUARDO; FERNÁNDEZ, BELISARIO ENRIQUE; CHOI, MARCELO ROBERTO

METABOLISM-CLINICAL AND EXPERIMENTAL

W B SAUNDERS CO-ELSEVIER INC

Año: 2018 vol. 85 p. 271 - 285

0026-0495

Background: The renin angiotensin system (RAS) and the renal dopaminergic system (RDS) act as autocrine and paracrine systems to regulate renal sodium management and inflammation and their alterations have been associated to hypertension and renal damage.Nearly 30?50% of hypertensive patients have insulin resistance (IR),with a strong correlation between hyperinsulinemia and microalbuminuria.Objective: The aimof this studywas to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), aswell as to establish their prevention,by pharmacological inhibition of RAS with losartan.Materials/Methods: Ninety-six male Sprague-Dawley ratswere randomly divided into four groups and studied at 4, 8 and 12 weeks: control group (C4, C8 and C12; tap water to drink); fructose-overloaded group (F4, F8 and F12; 10% w/v fructose solution to drink); losartan-treated control (L) group (L4, L8 and L12; losartan 30 mg/kg/day,in drinking water); and fructose-overloaded plus losartan group (F+L4, F+L8 and F+L12, in fructose solution).Results: FO inducedmetabolic and hemodynamic alterations as well as an imbalance between RAS and RDS, characterized by increased renal angiotensin II levels and AT1R overexpression, reduced urinary excretion of dopamine, increased excretion of L-dopa (increased L-dopa/dopamine index) and down-regulation of D1R and tubular dopamine transporters OCT-2, OCT-N1 and total OCTNs. This imbalance was accompanied by an overexpression of renal tubular Na+, K+-ATPase, pro-inflammatory (NF-kB, TNF-α, IL-6) and pro-fibrotic (TGF-β1 and collagen) markersand by renal damage (microalbuminuria and reduced nephrin expression). Losartan prevented the metabolic and hemodynamic alterations induced by FO from week 4. Increased urinary L-dopa/dopamine index and decreased D1R renal expression associated to FO were also prevented by losartan since week 4. The same pattern was observed for renal expression of OCTs/OCTNs, Na+, K+-ATPase, pro-inflammatory and pro-fibroticmarkers from week 8. The appearance of microalbuminuria and reduced nephrin expression was prevented by losartan at week 12.Conclusion: The results of this study provide new insight regarding the mechanisms by which a pro-hypertensive and pro-inflammatory system, such as RAS, downregulates another anti-hypertensive and anti-inflammatory system such as RDS. Additionally, we propose the use of L-dopa/dopamine index as a biochemical marker of renal dysfunction in conditions characterized by sodiumretention, IR and/or hypertension, and as a predictor of response to treatment and follow-up of these processes.