Renal effects of long-term leptin infusion and preventive role of losartan treatment in rats.
BACKGROUND
Leptin has direct and indirect effects on renal pathophysiological characteristics. In the present study, the effects of long-term leptin infusion on the renal hemodynamics, renal excretory functions, and the expression of transforming growth factor-beta (TGF-beta), plasma endothelin-1 (ET-1) levels, and preventive effects of the angiotensin II type 1 receptor antagonist, losartan, on these renal changes were evaluated.


METHODS
The study was performed by using forty Wistar albino rats. On day 0, osmotic mini-pumps filled with leptin or placebo were intraperitoneally placed under sterile conditions. The rats in Group L (Leptin group, n=15) and Group LL (Leptin-losartan group, n=15) were given recombinant murine leptin at a rate of 250 ng per hour for 28 days. Control rats (Group C, n=10) were administered placebo at the same infusion rate. The rats in Group LL were also administered losartan (10 mg kg(-1) d(-1)) perorally for 28 days. On day 28, the rats were placed in metabolic cages, and the food and water intakes were determined, and the urine was collected for 24 h. At the end of the study, systolic blood pressure (SBP), diastolic blood pressure (DBP) were determined directly from the left femoral artery, and renal blood flow (RBF) was recorded indirectly using a laser Doppler flow module.


RESULTS
Leptin infusion did not produce any changes in systemic arterial blood pressures and urinary flow rate. The rates of creatinine (Cr), sodium (Na), and protein excretions of the animals infused leptin were significantly increased. The urinary Cr and Na excretions were decreased, while the urinary protein excretion was normalized with the losartan treatment. The rats infused leptin had also higher circulating ET-1 levels. ET-1 levels were also reversed to the normal values with the losartan treatment. Renal TGF-beta1 expression was determined immunohistochemically, and it was more prominent in the renal tubules from the rats treated with leptin. The losartan treatment had no effect on renal TGF-beta1 expression.


CONCLUSIONS
Our results indicate that pathophysiological increases in plasma leptin concentrations cause enhanced renal Na, Cr and protein excretions, and high circulating ET-1 levels. Na and Cr excretions were decreased, while proteinuria and plasma ET-1 levels were normalized by losartan treatment, suggesting that renin-angiotensin system activation may have a role in leptin induced renal changes. TGF-beta1 may have an important role in leptin induced nephropathy.
Gunduz
Zubeyde
Z
Erciyes University, Medical Faculty, Department of Pediatrics, 38039, Kayseri, Turkey. zubeydeg@erciyes.edu.tr
Dursun
Nurcan
N
Akgun
Hulya
H
Ozturk
Figen
F
Okur
Hamit
H
Koc
Nedret
N
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000517:prevention & control; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D019808:Losartan / Q000627:therapeutic use*; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014554:Urination / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D020738:Leptin; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012964:Sodium; D003404:Creatinine; D019808:Losartan