Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN)

Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses

Background: Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. Aim: To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. Methods: DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Results: Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease - that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor β1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. Conclusion: This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.Peer Reviewe

Comparative data among control kidneys (from expanded-criteria donors [ECD] and patients with stable renal function), preimplant kidneys from ECDs, and transplanted kidneys from patients with ATN.

<p>ECD: Expanded-criteria donor with ATN; ATN: Acute tubular necrosis. Values are expressed as mean ± standard deviation.</p>*<p>P = 0.0001 one-way ANOVA test and <i>post hoc</i> with Bonferroni test.</p>†<p>Transplant protocol biopsies with stable renal function; NS: Non-significant.</p

Clinical variables according to nuclear immunohistochemical expression of PARP-1 in human kidney biopsies.

<p>Values are expressed as mean ± standard deviation; NS: Non-significant.</p>*<p>Student's <i><u>t</u>-</i> test.</p

Representation of ROC curves using PARP-1 expression as state variable.

<p>Representation of ROC curves using PARP-1 expression as state variable.</p

PARP-1 expression in human kidneys using polymer peroxidase-based method.

<p>A) Absence of PARP-1 expression in tubular cell nuclei in transplant protocol biopsy of kidney with stable renal function and without ATN (×100). B) Moderate PARP-1 expression in tubular cells of ECD kidney biopsy with ATN (×200). C) Moderate PARP-1 expression in necrotic tubuli of posttransplant kidney biopsy with ATN (×200). D, E, F): Intense PARP-1 expression in various biopsies with severe ATN (D x200, and E, F ×400). G) Glomerular immunostaining in a case of severe ATN. Note nuclear immunostaining in capillary and Bowman's capsule (×400). H) Negative isotype control (x200).</p

Western-blot analysis of PARP-1 expression in kidney of C57BL/6 mice.

<p>A) Presence of PARP-1 expression in kidney of C57BL/6 Parp1^+/+ mice absence of PARP-1 in knockout mice; and evident increase in PARP-1 expression at 48 h of reperfusion. Note partial inhibition of PARP-1 after inoculation with 3-ABA at 6 h of reperfusion. B) Induction of protein poly(ADP-ribosyl)ation after renal IR and its total inhibition by PARP-1 with 3-ABA. +/+: C57BL/6 wild-type mouse; −/−: C57BL/6 Parp-1 knockout mouse; 3-ABA: 3-aminobenzamide; C: Control; IR: Ischemia-Reperfusion; R: Reperfusion.</p