Antiglucocorticoid RU38486 reduces net protein catabolism in experimental acute renal failure

Abstract

BackgroundIn acute renal failure, a pronounced net protein catabolism occurs that has long been associated with corticoid action. By competitively blocking the glucocorticoid receptor with the potent antiglucocorticoid RU 38486, the present study addressed the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting?MethodsRU 38486 was administered in a dose of 50 mg/kg/24 h for 48 h after operation to fasted bilaterally nephrectomized (BNX) male adult Wistar rats and sham operated (SHAM) controls. Protein turnover was evaluated by high performance liquid chromatography (HPLC) of amino acid efflux in sera from isolated perfused hindquarters of animals treated with RU 38486 versus untreated controls.ResultsAdministration of RU 38486 reduces the total amino acid efflux (TAAE) by 18.6% in SHAM and 15.6% in BNX and efflux of the indicator of net protein turnover, phenylalanine (Phe) by 33.3% in SHAM and 13% in BNX animals as compared to the equally operated, but untreated animals. However, the significantly higher protein degradation observed in BNX (0.6 ± 0.2 nmol/min/g muscle) versus SHAM (0.2 ± 0.1 nmol/min/g muscle) rats, as demonstrated by the marker of myofribrillar proteolytic rate, 3-Methylhistidine (3 MH) remains unaffected by administration of RU 38486 (0.5 ± 0.1 v. 0.2 ± 0.1 nmol/min/g muscle in BNX v. SHAM).ConclusionRU 38486 does not act on changes of muscular protein turnover specific to uremia but reduces the effect of stress- stimulated elevated corticosterone secretion arising from surgery and fasting. A potentially beneficial effect against stress- induced catabolism in severe illness can be postulated that merits further study.

Association Between ACE Gene Insertion (I)/Deletion (D) Polymorphism and Primary Hypertension in Turkish Patients of Trakya Region

“…Several studies have shown a high prevalence of the DD genotype among patients with primary hypertension (6). On the other hand, researches have shown no differences in the allele frequencies and genotype distributions of ACE gene polymorphisms between the control and hypertension group (14). In our study, the overall frequencies of the genotypes II, ID, and DD were 31.9, 36.2, and 31.9, respectively in men, and 17.8, 51.1, and 31.1 respectively in women.…”

Molecular Patterns in Acute Pancreatitis Reflect Generalizable Endotypes of the Host Response to Systemic Injury in Humans

“…2A), here either gene or metabolite, was cross-referenced with publicly available resources (Supplementary Table 5, http://links.lww.com/SLA/C177). More specifically, for endotype A, prominent features consisted of: N-acetyl-3-methylhistidine and N-acetyl-1-methylhistidine—increased after muscle myofibrillar proteolysis and in renal failure 32 ; XIRP1—encoding Xin, a muscle-specific actin binding protein upregulated within 12 hours of injury 33 ; and MAP3K6—a mitogen-activated protein kinase kinase involved in apoptosis signaling 34 . Endotype B defining features were: complement factor H-related protein; HOXD3—upregulation of which increases immune cell adherence by upregulating glycoprotein IIb/IIIa 35 ; TRIM48—integral to interferon-γ signaling and oxidative stress-responsive cell death via apoptosis signal-regulating kinase 1 36 ; PPP1R3A 37 ; and REG3A—which encodes a bactericidal C-type lectin known commonly as pancreatitis-associated protein that, among multiple actions, alters the gut microbiome, and regulates gastrointestinal inflammation 38 (Fig.…”

“…For the HPB endotype, the thematic features were CELA2A -pancreatic elastase 2; UDP-glucuronosyltransferase -which is associated with Gilbert-type hyperbilirubinemia 29,30 ; and SLCO1B7 -a liver-specific organic anion transporter involved in bile secretion. The catabolic endotype was named for the following prominent features: N-acetyl-3-methylhistidine and N-acetyl-1-methylhistidine -increased after muscle myofibrillar proteolysis and in renal failure 31 ; SLC16A8 -a lactate and ketone body transporter; XIRP1 -encoding Xin, a muscle-specific actin binding protein upregulated within 12 hours of injury 32 ; and MAP3K6 -a mitogen-activated protein kinase kinase involved in apoptosis signalling 33 . The innate immune endotype defining features were: complement factor H-related protein -a heparin-binding protein involved in complement regulation; inositol-1-phosphate -the basis of inositol signalling; HOXD3 -upregulation of which increases immune cell adherence by upregulating glycoprotein IIb/IIIa 34 ; TRIM48 -integral to interferon-g signaling and oxidative stress-responsive cell death via apoptosis signal-regulating kinase 1 35 ; PPP1R3A -which has a genetic association with type 2 DM and familial partial lipodystrophy 3 36 ; and REG3A -which encodes a bactericidal C-type lectin known commonly as pancreatitis-associated protein that, among multiple actions, alters the gut microbiome and regulates gastrointestinal inflammation 37 (Figure 2a).…”

Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry

“…In order to define the role of corticoid action better in uremic patients with muscle degradation, he administered mifepristone (50 mg/kg/24 h given twice) to fasted nephrectomised male rats and to sham operated controls. Mondry [67] found that the administration of RU 486 reduced the total amino acid efflux by 18.6 and 15.6% and the efflux of phenylalanine by 33.3 and and 13%, respectively, in sham and treated animals compared to the equally operated but untreated animals. At the same time, the significantly higher protein degradation observed in treated and nephrectomised animals versus the sham group remained unaffected by mifepristone.…”

“…For this reason, Mondry [67] came up with the hypothesis that mifepristone, by competitively blocking glucocorticoid receptors, may have a positive impact in patients with acute renal failure. In order to define the role of corticoid action better in uremic patients with muscle degradation, he administered mifepristone (50 mg/kg/24 h given twice) to fasted nephrectomised male rats and to sham operated controls.…”