Natalia Lucía Rukavina Mikusic1, Nicolás Martín Kouyoumdzian2, Ana Uceda3, Julieta Sofía Del Mauro4, Marcela Pandolfo5, Mariela Mercedes Gironacci6, Ana María Puyó7, Jorge Eduardo Toblli8, Belisario Enrique Fernández9, Marcelo Roberto Choi10. 1. CONICET, Universidad de Buenos Aires, Instituto de Investigaciones Cardiológicas (ININCA), Marcelo T. de Alvear 2270, C1122AAJ City of Buenos Aires (CABA), Buenos Aires, Argentina; Universidad de Buenos Aires, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Junín 956, C1113AAD CABA, Buenos Aires, Argentina. Electronic address: naty_rkv@hotmail.com. 2. CONICET, Universidad de Buenos Aires, Instituto de Investigaciones Cardiológicas (ININCA), Marcelo T. de Alvear 2270, C1122AAJ City of Buenos Aires (CABA), Buenos Aires, Argentina; Universidad de Buenos Aires, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Junín 956, C1113AAD CABA, Buenos Aires, Argentina. 3. Hospital Alemán, Laboratorio de Medicina Experimental, Av Pueyrredón 1640, C1118AAT CABA, Buenos Aires, Argentina. 4. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de Farmacología, Junín 956, C1113AAD CABA, Buenos Aires, Argentina. 5. Universidad de Buenos Aires, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Junín 956, C1113AAD CABA, Buenos Aires, Argentina. 6. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Cátedra de Química Biológica, Junín 956, C1113AAD CABA, Buenos Aires, Argentina. 7. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Anatomía e Histología, Junín 956, C1113AAD CABA, Buenos Aires, Argentina. 8. CONICET, Universidad de Buenos Aires, Instituto de Investigaciones Cardiológicas (ININCA), Marcelo T. de Alvear 2270, C1122AAJ City of Buenos Aires (CABA), Buenos Aires, Argentina; Hospital Alemán, Laboratorio de Medicina Experimental, Av Pueyrredón 1640, C1118AAT CABA, Buenos Aires, Argentina. 9. CONICET, Universidad de Buenos Aires, Instituto de Investigaciones Cardiológicas (ININCA), Marcelo T. de Alvear 2270, C1122AAJ City of Buenos Aires (CABA), Buenos Aires, Argentina; Universidad de Buenos Aires, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Junín 956, C1113AAD CABA, Buenos Aires, Argentina; Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Av. Gral Las Heras 2191, C1127AAD CABA, Buenos Aires, Argentina. 10. CONICET, Universidad de Buenos Aires, Instituto de Investigaciones Cardiológicas (ININCA), Marcelo T. de Alvear 2270, C1122AAJ City of Buenos Aires (CABA), Buenos Aires, Argentina; Universidad de Buenos Aires, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Junín 956, C1113AAD CABA, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Anatomía e Histología, Junín 956, C1113AAD CABA, Buenos Aires, Argentina; Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Av. Gral Las Heras 2191, C1127AAD CABA, Buenos Aires, Argentina.
Abstract
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 aim of this study was to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), as well as to establish their prevention, by pharmacological inhibition of RAS with losartan. MATERIALS/ METHODS: Ninety-six male Sprague-Dawley rats were 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 induced metabolic 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) markers and 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-fibrotic markers 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 sodium retention, IR and/or hypertension, and as a predictor of response to treatment and follow-up of these processes.
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 hypertensivepatients have insulin resistance (IR), with a strong correlation between hyperinsulinemia and microalbuminuria. OBJECTIVE: The aim of this study was to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), as well as to establish their prevention, by pharmacological inhibition of RAS with losartan. MATERIALS/ METHODS: Ninety-six male Sprague-Dawley rats were 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 induced metabolic 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) markers and 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-fibrotic markers 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 sodium retention, IR and/or hypertension, and as a predictor of response to treatment and follow-up of these processes.
Authors: Nicolás M Kouyoumdzian; Natalia L Rukavina Mikusic; Gabriel D Robbesaul; Susana B Gorzalczany; Andrea Carranza; Verónica Trida; Belisario E Fernández; Marcelo R Choi Journal: Hypertens Res Date: 2020-09-16 Impact factor: 3.872