Abstract
Renal development in rodents, unlike in humans, continues during early postnatal period. We aimed to evaluate whether the pharmacological inhibition of Endothelin system during this period affects renal development, both at structural and functional level in male and female rats. Newborn rats were treated orally from postnatal day 1 to 20 with vehicle or bosentan (Actelion, 20 mg/kg/day), a dual endothelin receptor antagonist (ERA). The animals were divided in 4 groups: control males, control females, ERA males and ERA females. At day 21, we evaluated renal function, determined the glomerular number by a maceration method and by morphometric analysis and evaluated possible structural renal alterations by three methods: 〈alpha〉-Smooth muscle actin (α-SMA) immunohistochemistry, Masson's trichrome and Sirius red staining. The pharmacological inhibition of Endothelin system with a dual ERA during the early postnatal period of the rat did not leads to renal damage in the kidneys of male and female rats. However, ERA administration decreased the number of glomeruli, the juxtamedullary filtration surface area and the glomerular filtration rate and increased the proteinuria. These effects could predispose to hypertension or renal diseases in the adulthood. On the other hand, these effects were more pronounced in male rats, suggesting that there are sex differences that could be greater later in life. These results provide evidence that Endothelin has an important role in rat renal postnatal development. However these results do not imply that the same could happen in humans, since human renal development is complete at birth.
Highlights
Endothelin (ET) system is represented by three structurally similar endogenous 21-aminoacid peptides named ET-1, ET-2 and ET-3, that activate two G-protein-coupled receptors ETA and ETB and two activating proteases [1]
The number of total glomeruli determined by the maceration method significantly decreased in ERA males (ERAm) vs control males (Cm) (Fig 1)
The treatment with the endothelin receptor antagonist (ERA) decreased the capilar glomerular area (CGA) to the same extent in male and female rats
Summary
Endothelin (ET) system is represented by three structurally similar endogenous 21-aminoacid peptides named ET-1, ET-2 and ET-3, that activate two G-protein-coupled receptors ETA and ETB and two activating proteases [1]. Each isoform is encoded by a separate gene and both their synthesis and secretion are highly regulated at the transcriptional level by hormonal and environmental factors [2]. The different ET isoforms and the other components of this system are widely expressed in the body in most tissues, being ET-1 the predominant isoform [3,4]. At the renal level ET modulates blood flow, sodium and water excretion and acid-base balance [5]. It is well known that ET stimulates the transcription of different genes promoting mesangial glomerular and vascular smooth muscle cells proliferation, in addition to its ability to promote the synthesis of extracellular matrix [6]
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