Rapidly progressive glomerulonephritis (RPGN) is a clinical a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern (“crescents”) with accumulation of T cells and macrophages, and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 days after the induction of experimental RPGN. This suggests that targeting the HB-EGF/EGFR pathway could also be beneficial for treatment of human RPGN.

PD-L1 expression was higher in SC than in NSCLC as well as immune-cell infiltration by TCD3 cells and macrophages. This suggests that targeting the PD-1/PD-L1 pathway could represent a new potential therapy.

A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies. H ypertension frequently is complicated by the development of chronic renal failure, a complex pathology that is initiated by inflammatory events that evolve to increased synthesis and accumulation of extracellular matrix (ECM; mainly collagens) within the renal tissue and lead over time to loss of function and ESRD. To date, no efficient treatment that can stop or, even more desirable, reverse the decline of renal function exists. Therefore, the understanding of the systems and/or mechanisms that are involved in the development of renal vascular inflammation and fibrosis will provide valuable information to design specific pharmacologic targets to treat this incurable disease.Important advancements have been made regarding the mechanisms that are involved in the development of chronic renal failure. These studies focused mainly in the systems or agents that promote ECM synthesis and progression of renal disease. We and other investigators, for instance, clearly identified and characterized the signaling pathways that vasoconstrictor peptides are using to activate collagen synthesis (1-4). Less is known about the mechanisms regarding the postsynthesis regulation of ECM, such as matrix anchoring and interactions with the cell membrane.Among the systems that interact with the ECM are the discoidin domain receptors (DDR). They are the first identified receptor tyrosine kinases that bind directly to the ECM (5). DDR1 binds all types of collagens and is widely expressed in a variety of tissues, including vascular smooth m...