Type 1 diabetes is associated with reduced vascular repair, as indicated by impaired wound healing and reduced collateral formation in ischemia. Recently, endothelial progenitor cells (EPCs) have been identified as important regulators of these processes. We therefore explored the concept that EPCs are dysfunctional in diabetes. The number of EPCs obtained from type 1 diabetic patients in culture was 44% lower compared with age-and sex-matched control subjects (P < 0.001). This reduction was inversely related to levels of HbA 1c (R ‫؍‬ ؊0.68, P ‫؍‬ 0.01). In addition, we demonstrated that patient EPCs were also impaired in function using an in vitro angiogenesis assay. Conditioned media from patient EPCs were significantly reduced in their capacity to support endothelial tube formation in comparison to control EPCs. Therefore, despite culturing the EPCs under normoglycemic conditions, functional differences between patient and control EPCs were maintained. Our findings demonstrate that adverse metabolic stress factors in type 1 diabetes are associated with reduced EPC numbers and angiogenicity. We hypothesize that EPC dysfunction contributes to the pathogenesis of vascular complications in type 1 diabetes. Diabetes 53: 195

The incidence of cardiac failure and chronic renal failure is increasing and it has now become clear that the co-existence of the two problems has an extremely bad prognosis. We propose the severe cardiorenal syndrome (SCRS), a pathophysiological condition in which combined cardiac and renal dysfunction amplifies progression of failure of the individual organ, so that cardiovascular morbidity and mortality in this patient group is at least an order of magnitude higher than in the general population. Guyton has provided an excellent framework describing the physiological relationships between cardiac output, extracellular fluid volume control, and blood pressure. While this model is also sufficient to understand systemic haemodynamics in combined cardiac and renal failure, not all aspects of the observed accelerated atherosclerosis, structural myocardial changes, and further decline of renal function can be explained. Since increased activity of the renin-angiotensin system, oxidative stress, inflammation, and increased activity of the sympathetic nervous system seem to be cornerstones of the pathophysiology in combined chronic renal disease and heart failure, we have explored the potential interactions between these cardiorenal connectors. As such, the cardiorenal connection is an interactive network with positive feedback loops, which, in our view, forms the basis for the SCRS.

The kidney displays highly efficient autoregulation so that under steady-state conditions renal blood flow (RBF) is independent of blood pressure over a wide range of pressure. Autoregulation occurs in the preglomerular microcirculation and is mediated by two, perhaps three, mechanisms. The faster myogenic mechanism and the slower tubuloglomerular feedback contribute both directly and interactively to autoregulation of RBF and of glomerular capillary pressure. Multiple experiments have been used to study autoregulation and can be considered as variants of two basic designs. The first measures RBF after multiple stepwise changes in renal perfusion pressure to assess how a biological condition or experimental maneuver affects the overall pressure-flow relationship. The second uses time-series analysis to better understand the operation of multiple controllers operating in parallel on the same vascular smooth muscle. There are conceptual and experimental limitations to all current experimental designs so that no one design adequately describes autoregulation. In particular, it is clear that the efficiency of autoregulation varies with time and that most current techniques do not adequately address this issue. Also, the time-varying and nonadditive interaction between the myogenic mechanism and tubuloglomerular feedback underscores the difficulty of dissecting their contributions to autoregulation. We consider the modulation of autoregulation by nitric oxide and use it to illustrate the necessity for multiple experimental designs, often applied iteratively.

It is now established that all of the components necessary for the local formation of angiotensin II (ANG II) coexist in the kidney and can alter local ANG II production rate. However, data on ANG II concentrations in different compartments within the kidney are limited. Recently, proximal tubule fluid ANG II concentrations in the nanomolar range were reported. Using an ANG II radioimmunoassay procedure with enhanced sensitivity, we performed experiments to explore proximal tubular fluid ANG II levels further and to determine the source of the ANG II. Total free-flow proximal tubular fluid samples (n = 11) had an average ANG II concentration of 13 +/- 2 nM. These concentrations were similar (10 +/- 2 nM) in samples collected into pipettes containing the inhibitors enalaprilat and EDTA (n = 17). Fluid collected from blocked proximal tubules that were perfused with artificial tubular fluid showed similar ANG II concentrations both in the presence (22 +/- 3 nM) and absence (22 +/- 4 nM) of the angiotensin-converting-enzyme inhibitor, enalaprilat, in the perfusate. Plasma ANG II concentrations were much lower and averaged 155 +/- 26 pM. Isotonic saline expansion lowered plasma ANG II levels to 30 +/- 5 pM (P < 0.01) but did not significantly decrease intraluminal ANG II (8 +/- 1 nM). These data provide further evidence that intratubular ANG II concentrations are in the nanomolar range and are regulated independently of the plasma ANG II levels. The data obtained from perfused tubules indicate that the proximal tubule adds substantial amounts of ANG II or a precursor into the tubular lumen.

No abstract