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. We show that SMOC2 is critically involved in kidney fibrosis progression because transgenic mice overexpressing SMOC2 exhibit significantly enhanced tubulointerstial kidney fibrosis whereas SMOC2 knockout mice are protected from kidney fibrosis development. Furthermore, our preliminary data suggests that inhibition of SMOC2 in vitro and in vivo using small interfering RNA (siRNA) protects from kidney fibrosis suggesting a critical pathogenic role of SMOC2 in initiation and progression of the disease. In cell culture experiments we found that SMOC2 activates matrix assembly signaling in the fibroblasts to stimulate stress fiber formation, proliferation and migration ? features typical of transitioning into myofibroblasts that are the the effector cells in fibrosis. Whereas, SMOC2 treatment of primary human proximal tubular epithelial cells significantly increases pro fibrotic factors along with an increase in cell size and a decrease in cell number ? features consistent with partial epithelial to mesenchymal transition phenotype. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Shreffler, Carol A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
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
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

Showing the most recent 10 out of 28 publications