Role of Wnt4/ß-catenin, Ang II/TGFß, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone.

Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/ß-catenin signaling, p-S536NF-κBp65, PPARγ, Ang II/TGF-ß, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/ß-catenin and pS536-NF-κBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-κBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARγ and TGF-ß, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the ß-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-κB, Ang II, ACE2, TGFß, and a modulation of Wnt4/ß-catenin pathway.

Endothelin ETA receptor/lipid peroxides/COX-2/TGF-ß1 signalling underlies aggravated nephrotoxicity caused by cyclosporine plus indomethacin in rats.

BACKGROUND AND PURPOSE: Cyclosporine (CSA) and non-steroidal anti-inflammatory drugs (NSAIDs) are co-prescribed for some arthritic conditions. We tested the hypothesis that this combined regimen elicits exaggerated nephrotoxicity in rats via the up-regulation of endothelin (ET) receptor signalling. EXPERIMENTAL APPROACH: The effects of a 10 day treatment with CSA (20 mg · kg(-1) · day(-1)), indomethacin (5 mg · kg(-1) · day(-1)) or their combination on renal biochemical, inflammatory, oxidative and structural profiles were assessed. The roles of ETA receptor and COX-2 pathways in the interaction were evaluated. KEY RESULTS: Oral treatment with CSA or indomethacin elevated serum urea and creatinine, caused renal tubular atrophy and interstitial fibrosis, increased renal TGF-ß1, and reduced immunohistochemical expressions of ETA receptors and COX-2. CSA, but not indomethacin, increased renal ET-1, the lipid peroxidation product malondialdehyde (MDA) and GSH activity. Compared with individual treatments, simultaneous CSA/indomethacin exposure caused: (i) greater elevations in serum creatinine and renal MDA; (ii) loss of the compensatory increase in GSH; (iii) renal infiltration of inflammatory cells and worsening of fibrotic and necrotic profiles; and (iv) increased renal ET-1 and decreased ETA receptor and COX-2 expressions. Blockade of ETA receptors by atrasentan ameliorated the biochemical, structural, inflammatory and oxidative abnormalities caused by the CSA/indomethacin regimen. Furthermore, atrasentan partly reversed the CSA/indomethacin-evoked reductions in the expression of ETA receptor and COX-2 protein. CONCLUSIONS AND IMPLICATIONS: The exaggerated oxidative insult and associated dysregulation of the ETA receptor/COX-2/TGF-ß1 signalling might account for the aggravated nephrotoxicity caused by the CSA/indomethacin regimen. The potential renoprotective effect of ETA receptor antagonism might be exploited therapeutically.

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: role of endothelin signaling.

The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ETA/ETB) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20 mg kg(-1) day(-1), 10 days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renal perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ETA (increases) and ETB (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5 mg kg(-1) day(-1)), celecoxib (10 mg kg(-1) day(-1)) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ETA/ETB receptor expressions. Selective blockade of ETA receptors by atrasentan (5 mg kg(-1) day(-1)) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ETB receptor blocker, 0.1 mg kg(-1) day(-1)) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ETA downregulation and ETB upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen.

Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-ß1/IL-2/COX-2/endothelin ET(B) receptor cascade.

Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET(B) receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-ß1, TGF-ß1). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(B) receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ETB receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-ß1/IL-2/COX-2 pathway and the endothelin ET(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats.

Human leukocyte antigen class I alleles can predict response to pegylated interferon/ribavirin therapy in chronic hepatitis C Egyptian patients.

BACKGROUND: Racial differences and broad spectrum response to anti-hepatitis C (anti-HCV) therapy suggest a possible role for host genetic diversity in treatment outcomes. We aim to determine the association and predictive value of certain human leukocyte antigen (HLA) class I alleles with either susceptibility to viral clearance or persistence following pegylated interferon (Peg-IFN) plus ribavirin therapy in chronic hepatitis C (HCV) genotype 4 patients in Egypt.  METHODS: This study included 200 unrelated chronic HCV patients who received Peg-IFN plus ribavirin therapy [112 patients with sustained virological response (SVR) and 88 non-responders (NR)]. Serological testing of HLA class I antigens (HLA-A and HLA-B alleles) were performed by standard complement-dependent microlymphocytotoxicity assay.  RESULTS: The frequency of HLA-A01 was significantly higher in SVR than in NR cases [OR: 0.51; 95% CI: 0.27-0.981; P = 0.042], while the frequency of alleles B38 (P = 0.011), B40 (P < 0.001) and B41 (P < 0.001) was significantly higher in NR cases (OR/95% CI: 7.05/(1.39-18.01), 10.31/3.14-36.1 . On logistic regression analysis, presence of the HLA-A01 allele was associated with SVR  (OR: 0.50; 95% CI: 0.28-0.89; P = 0.02) and HLA-B38 can predict non response to therapy (OR: 7.92; 95% CI: 1.67-37.54; P = 0.009) with an overall accuracy of 60%.Severe fibrosis (OR: 3.035; 95% CI: 1.521-6.091; P = 0.002), high viremia (OR: 2.69; 95% CI: 1.11-6.53; P = 0.005) and steatosis (OR: 2.1; 95% CI: 1.002-3.90; P = 0.041) predicted no response with an overall accuracy of 81.8%.  CONCLUSION: HLA-A01 and HLA-B38 alleles are associated with and may have a role in the outcome of response to Peg-IFN plus ribavirin therapy in Egyptian patients diagnosed with chronic HCV infection. The use of immunologic markers to predict the outcome of treatment may help pharmacogenetic personalization of treatment for HCV infection.