Fibrinogen (Fg) is a soluble, dimeric glycoprotein with a hexameric structure composed of three distinct pairs of disulfide-linked polypeptide chains (Fg1, Fg2 and Fg3). In genome-wide expression analysis we found Fg2 to be the second highest gene upregulated amongst 22,523 genes in rat kidney at 24 hours following 20 minutes of bilateral ischemia/reperfusion (I/R) injury. The mRNA levels and de novo protein synthesis in the kidney as well as urinary excretion of Fg is significantly increased following kidney injury in mice, rats and humans. Under normal conditions, Fg is expressed by epithelial and endothelial cells in the kidney and following injury the expression of Fg1 significantly increases on basolateral membrane of the tubular epithelial cells, localization of Fg3 changes from basolateral to apical membrane whereas over expression Fg2 is predominantly in the renal interstitium. Furthermore, Fg protein (0.5, 1 or 2 mg/ml) stimulates proliferation of kidney epithelial cells (HEK293 and LLCPK1) by 200 % in a dose dependent manner. Fg has been recognized as an important regulator of hemostasis, inflammation and wound healing however, there is very limited knowledge about the functional significance of Fg signaling in kidney epithelial cells and even less is known about the mechanisms of action of Fg1, Fg2 and Fg3 that function distinctively based on their molecular confirmations. Given the potential of Fg for signal transduction via a wide range of cellular receptors; its expression in kidney during homeostasis and its significant over expression after injury, we hypothesize that Fg maintains cellular differentiation during homeostasis, whereas kidney injury upregulates Fg triggering tissue repair. In the first aim we will conduct translational studies to characterize the cellular expression and urinary excretion of Fg and its chains Fg1, Fg2 and Fg3 following acute and chronic kidney injury. In the second aim we propose to analyze the mechanistic role of Fg in the processes associated with dedifferentiation, proliferation and cytoskeletal rearrangements of kidney tubular epithelial cells using in vitro genetic manipulation approaches.
The third aim will evaluate the critical role of Fg signaling in modulating kidney tissue repair using Fg null mice and will also test the efficacy of polypeptides of Fg (B215-42 and 3377-395) in animal models of kidney injury. Understanding Fg signal transduction in kidney regeneration following kidney damage may provide opportunities for early diagnosis, prevention, and therapeutic interventions.
Kidney disease is a major public health concern receiving increased global attention owing to the significantly increased prevalence of the disease and high mortality rates. The proposed studies aim at uncovering a novel pathway in the kidney that may aid in early detection as well as developing therapeutic strategies to resolve kidney damage.
| Monteiro, Maria B; Ramm, Susanne; Chandrasekaran, Vidya et al. (2018) A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation. J Am Soc Nephrol 29:2820-2833 |
| Cardenas-Gonzalez, Mariana; Srivastava, Anand; Pavkovic, Mira et al. (2017) Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy. Clin Chem 63:1515-1526 |
| Trivedi, Priyanka; Kumar, Ramya K; Iyer, Ashwin et al. (2017) Targeting Phospholipase D4 Attenuates Kidney Fibrosis. J Am Soc Nephrol 28:3579-3589 |
| Gerarduzzi, Casimiro; Kumar, Ramya K; Trivedi, Priyanka et al. (2017) Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation. JCI Insight 2: |
| Gerlach, Cory V; Vaidya, Vishal S (2017) MicroRNAs in injury and repair. Arch Toxicol 91:2781-2797 |
| Ramm, Susanne; Adler, Melanie; Vaidya, Vishal S (2016) A High-Throughput Screening Assay to Identify Kidney Toxic Compounds. Curr Protoc Toxicol 69:9.10.1-9.10.26 |
| Cárdenas-González, M; Osorio-Yáñez, C; Gaspar-Ramírez, O et al. (2016) Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1. Environ Res 150:653-662 |
| Prozialeck, Walter C; VanDreel, Aaron; Ackerman, Christopher D et al. (2016) Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat. Biometals 29:131-46 |
| Pavkovic, Mira; Vaidya, Vishal S (2016) MicroRNAs and drug-induced kidney injury. Pharmacol Ther 163:48-57 |
| Jadhav, Shreyas; Ajay, Amrendra K; Trivedi, Priyanka et al. (2016) RNA-binding Protein Musashi Homologue 1 Regulates Kidney Fibrosis by Translational Inhibition of p21 and Numb mRNA. J Biol Chem 291:14085-94 |
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