Mechanisms of development of chronic kidney disease (CKD) a major health

Mechanisms of development of chronic kidney disease (CKD) a major health care burden are poorly understood. to early deterioration – coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant unfavorable EGFR isoform and hypoxia-inducible factor 1α (Hif-1α) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this cell proliferation was dramatically reduced in mice. These data are relevant to human CKD as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway Apatinib resulting in progressive renal failing and cystogenesis. Launch Whatever the preliminary Rabbit Polyclonal to MMP1 (Cleaved-Phe100). insult individual chronic kidney disease (CKD) is certainly characterized by intensifying destruction from the renal parenchyma and the increased loss of useful nephrons which eventually result in end-stage renal failing (ESRF). CKD represents an internationally concern: in america 102 567 sufferers started dialysis in 2003 (341 sufferers/million each year) (1) and equivalent rates were within developing countries and specifically ethnic groupings (2). Nevertheless these numbers certainly are a small fraction Apatinib from the millions of sufferers who are believed to involve some amount of renal impairment. In america the prevalence of chronically decreased kidney function is certainly 11% of adults (3). Understanding the pathophysiology of Apatinib CKD development is an integral problem for medical preparation therefore. The mechanisms of CKD progression are understood poorly. It’s been shown that reduction of the number of functional nephrons triggers molecular and cellular events promoting compensatory growth of the remaining ones (4). In some cases this compensatory process becomes pathological with the development of renal lesions and ESRF. Even though pathophysiology of compensation and progression is usually complex unregulated proliferation of glomerular tubular and interstitial cells may promote the development of glomerulosclerosis tubular cysts and interstitial fibrosis (5-7). The molecular programs that control this cascade of events are largely unknown. Attempts to dissect the molecular basis of CKD have been facilitated by the development of several experimental models of renal deterioration. Apatinib Among these the remnant kidney model is usually a mainstay since nephron reduction characterizes the development of most human CKD. Consequently this model recapitulates many features of human CKD including hypertension proteinuria and glomerular and tubulointerstitial lesions. Over the last 50 years this model has led to the discovery of crucial pathways and more importantly to the design of therapeutic strategies to slow the progression of CKD such as the widely clinically used renin-angiotensin inhibitors (8). More recently studies in various mouse strains have highlighted the importance of genetic factors in the development of experimental nephron reduction (9-11). We previously showed that the course and extent of renal lesions following nephron reduction vary significantly between two mouse strains: whereas FVB/N mice develop severe lesions (C57BL/6 × DBA2)F1 (hereafter referred to as B6D2F1) mice undergo compensation alone (12). Moreover we observed that this development of renal lesions paralleled the extent of cell proliferation (12). In fact once the compensatory growth is usually achieved a second wave of cell proliferation occurs only in the FVB/N strain. Hence this model offers a powerful tool to unravel the transcriptional programs and the Apatinib crucial mediators that are selectively activated long after nephron reduction to drive deterioration of the remaining nephrons. In the present study we performed an unbiased profiling of gene expression in the kidneys of the FVB/N and B6D2F1 mouse strains 2 months after nephron reduction when renal lesions develop and the second wave of cell proliferation is usually ongoing. We recognized a critical mediator of intensifying renal failure specifically the carrier proteins lipocalin 2 (Lcn2 or neutrophil gelatinase-associated lipocalin [NGAL] siderocalin 24 uterocalin) and uncovered what we should believe to be always a novel function of Lcn2. Furthermore we elucidated a distinctive molecular pathway where activation of EGFR leads to.