Ischemia/reperfusion (I/R) leads to Acute Kidney Injury. HIF-1α is a key factor during organ response to I/R. We previously demonstrated that HIF-1α is induced during renal reperfusion, after ischemia. Here we investigate the role of HIF-1α and the HIF-1α dependent mechanisms in renal repair after ischemia. By interference of HIF-1α in a rat model of renal I/R, we observed loss of expression and mis-localization of e-cadherin and induction of α-SMA, MMP-13, TGFβ, and collagen I. Moreover, we demonstrate that HIF-1α inhibition promotes renal cell infiltrates by inducing IL-1β, TNF-α, MCP-1 and VCAM-1, through NFkB activity. In addition, HIF-1α inhibition induced proximal tubule cells proliferation but it did not induce compensatory apoptosis, both in vivo. In vitro, HIF-1α knockdown in HK2 cells subjected to hypoxia/reoxygenation (H/R) promote cell entry into S phase, correlating with in vivo data. HIF-1α interference leads to downregulation of miR-127-3p and induction of its target gene Bcl6 in vivo. Moreover, modulation of miR-127-3p in HK2 cells subjected to H/R results in EMT regulation: miR127-3p inhibition promote loss of e-cadherin and induction of α-SMA and collagen I. In conclusion, HIF-1α induction during reperfusion is a protector mechanism implicated in a normal renal tissue repair after I/R.

Carcinomas, such as colon cancer, initiate their invasion by rescuing the innate plasticity of both epithelial cells and stromal cells. Although Snail is a transcriptional factor involved in the Epithelial-Mesenchymal Transition, in recent years, many studies have also identified the major role of Snail in the activation of Cancer-Associated Fibroblast (CAF) cells and the remodeling of the extracellular matrix. In CAFs, Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant. High expression of both SNAI1 and PDGF receptors is associated with poor prognosis in cancer patients, but the mechanism(s) that underlie these connections are not understood. In this study, we demonstrate that PDGF-activated fibroblasts stimulate extracellular matrix (ECM) fiber remodeling and deposition. Furthermore, we describe how SNAI1, through the FAK pathway, is a necessary factor for ECM fiber organization. The parallel-oriented fibers are used by endothelial cells as “tracks”, facilitating their activation and the creation of tubular structures mimicking in vivo capillary formation. Accordingly, Snail1 expression in fibroblasts was required for the co-adjuvant effect of these cells on matrix remodeling and neoangiogenesis when co-xenografted in nude mice. Finally, in tumor samples from colorectal cancer patients a direct association between stromal SNAI1 expression and the endothelial marker CD34 was observed. In summary, our results advance the understanding of PDGF/SNAI1-activated CAFs in matrix remodeling and angiogenesis stimulation.

Background Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is a chronic relapsing and remitting autoimmune disease. Urinary soluble CD163 (usCD163) has been proposed as a biomarker of active renal vasculitis. We aimed to assess the potential usefulness of usCD163 for diagnosing renal relapse in patients with ANCA-associated glomerulonephritis. Methods One hundred and fifty-six samples from 47 patients with ANCA-associated glomerulonephritis belonging to two different cohorts (incident and prevalent) and 20 healthy controls were studied. Patients from the incident cohort were prospectively followed up, and usCD163 concentrations were measured every 3 months. Renal relapses were identified and changes in usCD163 concentrations were analysed. Results Normalized usCD163 concentrations were elevated at disease onset in all patients with active renal vasculitis, with a median concentration of 601 ng/mmol (interquartile range 221–1404 ng/mmol). On the other hand, usCD163 concentrations were undetectable among control patients with renal vasculitis in remission. Except for non-responders, usCD163 concentrations progressively decreased in all patients after treatment. In the presence of vasculitis relapse, there was a consistent increase in usCD163 concentrations, compared with previous values. The area under the receiver-operating characteristic curve of absolute and relative changes in usCD163 concentrations to identify relapse of ANCA-associated glomerulonephritis was 0.96 [95% confidence interval (CI) 0.91–1.00; P = 0.001] and 0.95 (95% CI 0.90–1.00; P = 0.001), respectively. Sensitivity and specificity for a relative increase of 20%, or an absolute increase of 20 ng/mmol, in usCD163 concentrations were 100% for both, and 89.3% and 87.5%, respectively. Urinary sCD163 concentrations significantly correlated with Birmingham Vasculitis Activity Score scores at Month 6 (r = 0.737; P = 0.006) and Month 12 (r = 0.804; P = 0.005). Conclusions usCD163 represents an accurate biomarker for the detection of active renal vasculitis and relapse. Its close association with disease activity provides additional information for monitoring treatment response.

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