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 NL; KOUYOUMDZIAN NM; UCEDA A; DEL MAURO J; PANDOLFO M; GIRONACCI MM; PUYÓ AM; TOBLLI JE; FERNÁNDEZ BE; CHOI MR

METABOLISM-CLINICAL AND EXPERIMENTAL

W B SAUNDERS CO-ELSEVIER INC

Lugar: Philadelphia; Año: 2018

0026-0495

Background: The renin angiotensin system (RAS) and the renal dopaminergic system(RDS) act as autocrine and paracrine systems to regulate renal sodiummanagement and inflammation and their alterations have been associated tohypertension and renal damage. Nearly 30-50% of hypertensive patients haveinsulin resistance (IR), with a strong correlation between hyperinsulinemia andmicroalbuminuria.Objective: The aim of this study was to demonstrate the existence of an imbalancebetween RAS and RDS associated to IR, hypertension and kidney damage induced byfructose overload (FO), as well as to establish their prevention, bypharmacological inhibition of RAS with losartan. Materials/Methods: Ninety-six male Sprague-Dawley rats were randomlydivided 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 andL12; losartan 30 mg/kg/day, in drinking water); and fructose-overloaded pluslosartan group (F+L4, F+L8 and F+L12, in fructose solution). Results: FO induced metabolic and hemodynamic alterations as well as an imbalancebetween RAS and RDS, characterized by increased renalangiotensin II levels and AT1R overexpression, reducedurinary excretion of dopamine, increased excretion of L-dopa (increasedL-dopa/dopamine index) and down-regulation of D1R and tubulardopamine transporters OCT-2, OCT-N1 and total OCTNs. This imbalance wasaccompanied by an overexpression of renal tubular Na+, K+-ATPase,pro-inflammatory (Nf-KB, TNF-α, IL-6) and pro-fibrotic (TGF-B1 and collagen)markers and by renal damage (microalbuminuria and reduced nephrin expression). Losartanprevented the metabolic and hemodynamic alterations induced by FO from week 4.Increased urinary L-dopa/dopamine index and decreased D1R renal expressionassociated to FO were also prevented by losartan since week 4. The same patternwas observed for renal expression of OCTs/OCTNs, Na+, K+-ATPase,pro-inflammatory and pro-fibrotic markers from week 8. The appearance ofmicroalbuminuria and reduced nephrin expression were prevented by losartan atweek 12.Conclusion: The results of this study provide new insight regarding the mechanismsby 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 theL-dopa/dopamine index as a biochemical marker of renal dysfunction in statescharacterized by sodium retention, insulin resistance and/or hypertension, andas a predictor of response to treatment and follow-up of these processes.