Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury.

Damage to endothelial cells contributes to acute kidney injury (AKI) by causing impaired perfusion, while the permanent loss of the capillary network following AKI has been suggested to promote chronic kidney disease. Therefore, strategies to protect renal vasculature may impact both short-term recovery and long-term functional preservation post-AKI. Human adipose stromal cells (hASCs) possess pro-angiogenic and anti-inflammatory properties and therefore have been tested as a therapeutic agent to treat ischaemic conditions. This study evaluated hASC potential to facilitate recovery from AKI with specific attention to capillary preservation and inflammation. Male Sprague Dawley rats were subjected to bilateral ischaemia/reperfusion and allowed to recover for either two or seven days. At the time of reperfusion, hASCs or vehicle was injected into the suprarenal abdominal aorta. hASC-treated rats had significantly greater survival compared to vehicle-treated rats (88.7% versus 69.3%). hASC treatment showed hastened recovery as demonstrated by lower creatinine levels at 48 hrs, while tubular damage was significantly reduced at 48 hrs. hASC treatment resulted in a significant decrease in total T cell and Th17 cell infiltration into injured kidneys at 2 days post-AKI, but an increase in accumulation of regulatory T cells. By day 7, hASC-treated rats showed significantly attenuated capillary rarefaction in the cortex (15% versus 5%) and outer medulla (36% versus 18%) compared to vehicle-treated rats as well as reduced accumulation of interstitial alpha-smooth muscle actin-positive myofibroblasts. These results suggest for the first time that hASCs improve recovery from I/R-induced injury by mechanisms that contribute to decrease in inflammation and preservation of peritubular capillaries.

Polycythemia, capillary rarefaction, and focal glomerulosclerosis in two adolescents born extremely low birth weight and premature.

BACKGROUND: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs. CASE-DIAGNOSIS/TREATMENT: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction. CONCLUSIONS: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

A Boolean Model of Microvascular Rarefaction to Predict Treatment Outcomes in Renal Disease.

Despite advances in renovascular disease (RVD) research, gaps remain between experimental and clinical outcomes, translation of results, and the understanding of pathophysiological mechanisms. A predictive tool to indicate support (or lack of) for biological findings may aid clinical translation of therapies. We created a Boolean model of RVD and hypothesized that it would predict outcomes observed in our previous studies using a translational swine model of RVD. Our studies have focused on developing treatments to halt renal microvascular (MV) rarefaction in RVD, a major feature of renal injury. A network topology of 20 factors involved in renal MV rarefaction that allowed simulation of 5 previously tested treatments was created. Each factor was assigned a function based upon its interactions with other variables and assumed to be "on" or "off". Simulations of interventions were performed until outcomes reached a steady state and analyzed to determine pathological processes that were activated, inactivated, or unchanged vs. RVD with no intervention. Boolean simulations mimicked the results of our previous studies, confirming the importance of MV integrity on treatment outcomes in RVD. Furthermore, our study supports the potential application of a mathematical tool to predict therapeutic feasibility, which may guide the design of future studies for RVD.

The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats.

Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats (n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats (n = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, P < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels (r2 = -0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose (P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone (P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D.NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an α1-adrenergic antagonist) can reduce these complications and improve glycemic control.