# Role of SMOC2 in Kidney Fibrosis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $382,635

## Abstract

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 α-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.

## Key facts

- **NIH application ID:** 10151450
- **Project number:** 5R01ES017543-10
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Vishal S. Vaidya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,635
- **Award type:** 5
- **Project period:** 2011-09-07 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151450

## Citation

> US National Institutes of Health, RePORTER application 10151450, Role of SMOC2 in Kidney Fibrosis (5R01ES017543-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10151450. Licensed CC0.

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