Acyloxydiene-Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene-Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms.

The importance of albuminuria as opposed to proteinuria in predicting kidney outcomes in primary IgA nephropathy (IgAN) is not well established. From 2010 to 2012, 421 patients with biopsy-proven IgAN have been enrolled into the German Chronic Kidney Disease (GCKD) cohort, a prospective observational cohort study (N = 5217). Adjudicated endpoints included a Composite Kidney Endpoint (CKE) consisting of eGFR decline > 40%, eGFR < 15 ml/min/1.73 m² and initiation of kidney replacement therapy; the individual components of the CKE; and combined major adverse cardiac events (MACE), including nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. The associations between the incidence of CKE and baseline factors, including demographics, laboratory values and comorbidities were analyzed using the Cox proportional hazards regression model. The mean age at baseline of IgAN patients was 51.6 years (± 13.6) and 67% were male. Patient-reported duration of disease at baseline was 5.9 ± 8.1 years. Baseline median UACR was 0.4 g/g (0.1–0.8) and mean eGFR was 52.5 ± 22.4 mL/min/1.73m². Over a follow-up of 6.5 years, 64 (15.2%) experienced > 40% eGFR decline, 3 (0.7%) reached eGFR < 15 ml/min and 53 (12.6%) initiated kidney replacement therapy and 28% of the patients experienced the CKE. Albuminuria, with reference to < 0.1 g/g was most associated with CKE. Hazard ratios (95% CI) at UACR 0.1–0.6 g/g, 0.6–1.4 g/g, 1.4–2.2 g/g and > 2.2 g/g were 2.03 (1.02–4.05), 3.8 (1.92–7.5), 5.64 (2.58–12.33) and 5.02 (2.29–11-03), respectively. Regarding MACE, the presence of diabetes (HR = 2.53, 95% CI 1.11–5.78) was the most strongly associated factor, whereas UACR and eGFR did not show significant associations. In the GCKD IgAN sub-cohort more than every fourth patient experienced a CKE event within 6.5 years. Our findings support the use of albuminuria as a surrogate to assess the risk of poor kidney outcomes.

Acute tubular injury accounts for the most common intrinsic cause for acute kidney injury. Normally, the tubular epithelium is mitotically quiescent. However, upon injury, it can show a brisk capacity to regenerate and repair. The scattered tubular cell (STC) phenotype was discovered as a uniform reaction of tubule cells triggered by injury. The STC phenotype is characterized by a unique protein expression profile, increased robustness during tubular damage and increased proliferation. Nevertheless, the exact origin and identity of these cells have been unveiled only in part. Here, we discuss the classical concept of renal regeneration. According to this model, surviving cells dedifferentiate and divide to replace neighbouring lost tubular cells. However, this view has been challenged by the concept of a pre-existing and fixed population of intratubular progenitor cells. This review presents a significant body of previous work and animal studies using lineage-tracing methods that have investigated the regeneration of tubular cells. We review the experimental findings and discuss whether they support the progenitor hypothesis or the classical concept of renal tubular regeneration. We come to the conclusion that any proximal tubular cell may differentiate into the regenerative STC phenotype upon injury thus contributing to regeneration, and these cells differentiate back into tubular cells once regeneration is finished.