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Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable to ageing-related processes in human kidneys has also been described in Sprague-Dawley (SD) rats. The renin-angiotensin-system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease and is a successful therapeutic target. The discovery of angiotensin-(1-7) (Ang(1-7)), mainly produced by angiotensin-converting enzyme 2 (ACE2), and its receptor MAS offered a new view on the RAS. This ACE2/Ang(1-7)/MAS axis counteracts most deleterious actions of the RAS in the kidney. In order to evaluate if activation of this axis has a protective effect in ageing-induced kidney disease we generated a transgenic rat model (TGR(SM22hACE2)) overexpressing human ACE2 in vascular smooth muscle cells. These animals showed a specific transgene expression pattern and increased ACE2 activity in the kidney. Telemetric recording of cardiovascular parameters and evaluation of kidney function by histology and urine analysis revealed no alterations in blood pressure regulation and basal kidney function in young transgenic rats when compared to young SD rats. However, with ageing, SD rats developed a decline in kidney function characterized by severe albuminuria which was significantly less pronounced in TGR(SM22hACE2) rats. Concomitantly, we detected lower mRNA expression levels of kidney damage markers in aged transgenic animals. Thus, our results indicate that vascular ACE2-overexpression protects the kidney against ageing-induced decline in kidney function, supporting the kidney-protective role of the ACE2/Ang(1-7)/MAS axis.

ABSTRACT:Origen of Alexandria’s De principiis exerted enormous influence on early Christian writers, yet few works have been met with such a perplexingly varied and polemical reception, even up to our time. In this article, I propose a new reading of De principiis based on taking seriously Origen’s enduring preoccupation with movement and body throughout his work, in conjunction with the central relevance he accords to imitation. I argue that books 1 and 4 provide the framework in which the two cycles of the work are unfolding, thereby initiating the reader into the praxis of Origen’s ἐπιστήμη. It is then this praxis that is able to enlighten even notoriously obscure passages by uniting the ambiguities of “ἀρχή” in itself and finally leading human beings into the completion of themselves and the cosmos.

Elderly organ transplant recipients have remained underrepresented in clinical trials, despite representing a rapidly growing population. Here, we assessed age‐specific effects of CTLA4‐Ig (cytotoxic T‐lymphocyte antigen 4‐Ig), a fusion protein blocking costimulatory signaling between antigen‐presenting cells and T cells through CD28. Cardiac allografts in young mice (2‐3 months) treated with CTLA4‐Ig survived indefinitely, whereas 80% of old recipients (18 months) had lost their graft after 100 days. CTLA4‐Ig was also significantly less effective in older recipients of skin transplants. CTLA4‐Ig reduced CD4+central memory and effector memory T cells and diminished systemic interferon‐gamma levels only in young recipients. These differences corresponded to a reduced expression of CD28 on antigen‐experienced CD4+T cells in old mice. In support, adoptive transfer of old CD4+T cells that were transfected with a lentiviral vector inducing constant expression of CD28 accelerated the rejection of allogeneic skin grafts in young RAG2−/−recipient mice. Regulatory T cells (Tregs), in contrast, demonstrated an increased expression of CD28 with aging and CTLA4‐Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation, and diminished suppressive capacity of Tregs. These findings may prove to have unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients. Investigation of age‐specific effects of costimulatory blockade with CTLA4‐Ig reveals reduced immunosuppressive capacity in old recipient mice linked to a compromised ability to suppress CD28‐negative effector‐type CD4+ T cells and a disturbance of Treg suppressor activity.

Age-dependent immunosuppressive effects of rapamycin on alloimmune responses in a fully major-histocompatibility-complex-mismatched murine transplantation model. Supplemental digital content is available in the text.

Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge.

Obesity has become an increasing problem in healthcare worldwide with far-reaching consequences. More obese patients with irreversible end-stage organ failure undergo organ transplantation, and organs from obese donors are more frequently used. A growing body of evidence suggests more frequent postoperative complications and inferior patient and graft survival linked to obesity. More recently, adipose tissue has been linked to chronic inflammatory processes potentially impacting alloimmune responses and graft quality.