CLINICAL STUDY Direct effect of methylprednisolone on renal sodium and water transport via the principal cells in the kidney Thomas G Lauridsen, Henrik Vase, Jesper N Bech, Søren Nielsen 1 and Erling B Pedersen Department of Medical Research, Holstebro Hospital, University of Aarhus, DK-7500 Holstebro, Denmark and 1 Institute of Anatomy, The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark (Correspondence should be addressed to T G Lauridsen; Email: thomlaur@rm.dk) Abstract Background: Glucocorticoids influence renal concentrating and diluting ability. We tested the hypothesis that methylprednisolone treatment increased renal water and sodium absorption by increased absorption via the aquaporin-2 (AQP2) water channels and the epithelial sodium channels (ENaCs) respectively. Methods: The effect of methylprednisolone was measured during fasting in a randomized, placebo- controlled, single-blinded cross-over study of 15 healthy humans. The subjects received a standardized diet on day 1, fasted on day 2, and received 500 mg methylprednisolone intravenously on day 3. The effect variables were urinary excretions of AQP2 (u-AQP2), urinary excretion of the b-fraction of the ENaC (u-ENaC b ), cAMP (u-cAMP), prostaglandin E 2 (u-PGE 2 ), free water clearance (C H 2 O ), and fractional excretion of sodium (FE Na ), and plasma vasopressin (p-AVP), angiotensin II (p-Ang II), aldosterone (p-Aldo), atrial natriuretic peptide (p-ANP), and brain natriuretic peptide (p-BNP). Results: Methylprednisolone treatment increased u-AQP2, u-ENaC b , and p-AVP significantly, but did not change u-cAMP, C H 2 O , and FE Na . P-ANP increased during methylprednisolone treatment, but after the increase in u-AQP2 and u-ENaC b . U-PGE 2 , p-Ang II, and p-BNP were unchanged. Heart rate increased and diastolic blood pressure fell. Conclusions: Methylprednisolone increased u-AQP2 and u-ENaC. Neither the AVP–cAMP axis nor changes in the renin–angiotensin–Aldo system, or the natriuretic peptide system seems to bear a causal relationship with the increase in either u-AQP2 or u-ENaC. Most probably, the effect is mediated via a direct effect of methylprednisolone on the principal cells. The lack of decrease in urinary output and sodium reabsorption most likely can be attributed to the diuretic and natriuretic properties of the increased secretion of ANP. European Journal of Endocrinology 162 961–969 Introduction Glucocorticoids modulate the secretion of vasopressin (AVP). AVP secretion is inhibited in Cushing’s syndrome and during methylprednisolone treatment, which results in a reduced urinary concentrating ability. In Addison’s disease, AVP secretion is stimulated, and urinary diluting ability is reduced. However, in healthy subjects treated with methylprednisolone, plasma concentration of AVP (p-AVP) was severely suppressed, but urinary concentrating ability remained unchanged (1). Thus, glucocorticoid treatment has an AVP-indepen- dent effect on the renal capacity to excrete water. Aquaporin-2 (AQP2) trafficking mediates water transport across the apical cell membrane in the principal cells of the collecting ducts in the kidneys (2) . The short-term regulation by AVP involves activation of V 2 receptors and subsequent trafficking of AQP2 vesicles to the apical plasma membrane, resulting in increased water permeability and absorp- tion. The long-term regulation is due to a rapid change in AQP2 mRNA expression followed by a more slow AQP2 synthesis. From a theoretical point of view, several mechanisms could be involved in a non-AVP- mediated increase in urinary concentrating ability. First, inhibition of the prostaglandin receptors on the principal cells has a synergistic effect on AVP (3). Secondly, direct stimulation of cAMP in the principal cells will increase AQP2 trafficking to the apical membrane and facilitate water transport. Thirdly, glucocorticoids might directly stimulate AQP2 traffick- ing and/or AQP2 synthesis. Lastly, the activity of the renin–angiotensin–Aldo system and the natriuretic peptide system might be changed during glucocorticoid treatment, and subsequently renal water reabsorption. Cellular trafficking and synthesis of the epithelial sodium channels (ENaCs) are the pathways for sodium transport across epithelia, including the kidney European Journal of Endocrinology (2010) 162 961–969 ISSN 0804-4643 q 2010 European Society of Endocrinology DOI: 10.1530/EJE-10-0030 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 12/29/2021 12:11:20PM via free access