Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) such as collagen and fibronectin in and around damaged tissue, which can lead to permanent scarring, organ malfunction and, ultimately, death. Although we have advanced our understanding of the pathogenesis of kidney fibrosis the translation of these findings to humans has been limited and no proven therapeutic strategies can yet detect or prevent the disease progression. We discovered Secreted Protein Acidic and Rich in Cysteines (SPARC) related modular calcium binding 2 (SMOC2) to be amongst the highest upregulated genes in the kidneys of mice subjected to chronic progressive kidney fibrosis. The mRNA and protein levels of SMOC2 were confirmed to be increased (10 to 60-fold) in three mechanistically distinct mouse models of kidney fibrosis as well as in patients with biopsy-proven kidney fibrosis. In the human fibrotic kidney, SMOC2 was concentrated in epithelial cells of the tubular region while also dispersed around the ?-Smooth Muscle Actin positive myofibroblasts of the interstitial tissue. In cell culture experiments, recombinant SMOC2 activated fibroblasts to proliferate and migrate - features typical of transitioning into the effector cell of repair ? Myofibroblast. SMOC2 treatment of primary human proximal tubular epithelial cells significantly increased vimentin staining (a marker of epithelial cell de-differentiation) along with an increase in cell size ? typical of epithelial to mesenchymal transition (EMT); coupled with a decrease in cell number (features of the profibrotic TGF? pathway). We also found that transgenic mice overexpressing SMOC2 showed significantly enhanced tubulointerstitial fibrosis characterized by substantially higher myofibroblast activation, neutrophil infiltration and collagen accumulation following unilateral ureteral obstruction-induced kidney fibrosis. These results have led us to hypothesize that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney that plays a critical role in the reparative scaffold; whose continual presence leads to fibrosis. The objective here is to investigate how induction of SMOC2 in fibroblasts and epithelial cells regulate initiation and progression of kidney fibrosis and whether genetic or pharmacologic modulation of SMOC2 is capable of altering the ultimate outcome from kidney fibrosis. Given that there is no information on the functional significance of SMOC2 upregulation following kidney damage the proposed studies aim at uncovering a novel pathway which may provide opportunities for targeted therapies for patients with kidney fibrosis ? an unmet medical need.
Kidney fibrosis is a major public health concern receiving increased global attention owing to the significantly increased prevalence of the disease and high mortality rates. We have identified a novel protein called SMOC2 that plays a critical regulatory role in development and progression of fibrosis. We aim at understanding the function of SMOC2 as it will provide important insight into the molecular pathogenesis of kidney fibrosis and may identify SMOC2 as an important biomarker and a therapeutic target for chronic kidney disease.
| 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 |
| 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 |
| 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 |
| 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 |
| Craciun, Florin L; Bijol, Vanesa; Ajay, Amrendra K et al. (2016) RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis. J Am Soc Nephrol 27:1702-13 |
Showing the most recent 10 out of 17 publications
