We have identified a new type of growth factor called Ngal (lipocalin-2) which is a member of the lipocalin- superfamily. It is known that lipocalins bind and transport small chemicals ligands, but little has beenknown about Ngal, and some of its presumptive ligands have been disproved. We purified Ngal from liters of media conditioned by an embryonic cell line, which revealed a growthfactor with a reddish color. The cloned protein was also colored and x-ray crystallography of the cloned protein (R. Strong, Fred Hutchinson Cancer Research Center) showed that it contained a siderophore:Fe complex that it had bound during cloning. Using recombinant Ngal we could induce growth and conversion of mesenchymeinto epithelia, tubule and nephrons, but only when rNgal was loaded with this siderophore and iron. This suggested that Ngal's inductive action must have been due to its ligand, and we speculate that perhaps a mammalian versionof the siderophore is present in vivo. Ngal is one of the most overexpressed proteins in ischemic disease of the kidney (>1000 fold increases). It is also the earliest known protein to be increased in the urine and in the serum of ischemic and toxicdiseases of the kidney. In situ hybridization shows that Ngal is massively expressed by TALH and collecting ducts. In this grant we propose to study the activity of the endogenous Ngal protein. We will do this by completing an isolation of a small organic molecule that binds Ngal and binds iron. The Ngal ligand is found in mammalian urine. We will identify the structure of this compound using IR, NMR, Mass spectroscopyand x- ray crystallography. To further examine the function of Ngal in the kidney we have deleted its gene in a tissue specific manner. Because Ngal previously had a protective function in an ischemic model of the kidney, we will examine whether the Ngal knockout is more sensitive to ischemia reperfusion injury. We will test the hypothesis that the Ngal:urine siderophore complex removescatalytic iron and converselythe Ngal knockout contains more catalytic iron and iron mediated cell damage. The knockout will then be rescuedby exogenous Ngal or iron chelators. This work is important because it characterizes a novel growth factorthat is massively expressed by damaged renal epithelia and it evaluates a novel iron transport pathwaythat appears critical to Ngal function.
| Wang, Xueqiao; Zheng, Xiaoqing; Zhang, Juanlian et al. (2018) Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am J Physiol Renal Physiol 315:F1042-F1057 |
| Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51 |
| Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763 |
| Xu, Katherine; Rosenstiel, Paul; Paragas, Neal et al. (2017) Unique Transcriptional Programs Identify Subtypes of AKI. J Am Soc Nephrol 28:1729-1740 |
| Forster, Catherine S; Johnson, Kathryn; Patel, Viral et al. (2017) Urinary NGAL deficiency in recurrent urinary tract infections. Pediatr Nephrol 32:1077-1080 |
| Costanzo, Maria Rosa; Ronco, Claudio; Abraham, William T et al. (2017) Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research. J Am Coll Cardiol 69:2428-2445 |
| Schrezenmeier, E V; Barasch, J; Budde, K et al. (2017) Biomarkers in acute kidney injury - pathophysiological basis and clinical performance. Acta Physiol (Oxf) 219:554-572 |
| Werth, Max; Schmidt-Ott, Kai M; Leete, Thomas et al. (2017) Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. Elife 6: |
| Barasch, Jonathan; Hollmen, Maria; Deng, Rong et al. (2016) Disposal of iron by a mutant form of lipocalin 2. Nat Commun 7:12973 |
| Bao, Guan-Hu; Ho, Chi-Tang; Barasch, Jonathan (2015) The Ligands of Neutrophil Gelatinase-Associated Lipocalin. RSC Adv 5:104363-104374 |
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