Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, ␣ 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium.

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-␤ signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets. (Am J Pathol 2011, 178:911-923;

The incidence rate of AKI in hospitalized patients is increasing. However, relatively little attention has been paid to the association of AKI with long-term risk of adverse coronary events. Our study investigated hospitalized patients who recovered from de novo dialysis-requiring AKI between 1999 and 2008 using patient data collected from inpatient claims from Taiwan National Health Insurance. We used Cox regression with time-varying covariates to adjust for subsequent CKD and ESRD after discharge. Results were further validated by analysis of a prospectively constructed database. Among 17,106 acute dialysis patients who were discharged, 4869 patients recovered from dialysis-requiring AKI (AKI recovery group) and were matched with 4869 patients without AKI (non-AKI group). The incidence rates of coronary events were 19.8 and 10.3 per 1000 person-years in the AKI recovery and non-AKI groups, respectively. AKI recovery associated with higher risk of coronary events (hazard ratio [HR], 1.67; 95% confidence interval [95% CI], 1.36 to 2.04) and all-cause mortality (HR, 1.67; 95% CI, 1.57 to 1.79) independent of the effects of subsequent progression to CKD and ESRD. The risk levels of de novo coronary events after hospital discharge were similar in patients with diabetes alone and patients with AKI alone (P=0.23). Our results reveal that AKI with recovery associated with higher long-term risks of coronary events and death in this cohort, suggesting that AKI may identify patients with high risk of future coronary events. Enhanced postdischarge follow-up of renal function of patients who have recovered from temporary dialysis may be warranted. The incidence rate of AKI in hospitalized patients is increasing 1 and the number of deaths associated with dialysis-requiring AKI has more than doubled. 2 In hospitalized patients, AKI results in increased in-hospital and posthospitalization resource use. 3 Currently, the incidence rate of dialysis-requiring AKI is higher than the rate of ESRD, and its annual growth rate is as high as 10% in the United States. 4 Along with the advances in critical care medicine and dialysis technologies, the probability of being discharged alive after temporary AKI has been rising among hospitalized patients. 5 It has been noticed