S100A4 in Lupus Nephritis

Lupus nephritis (LN) occurs in up to 60% of adults and 80% of children with systemic lupus erythematosus (SLE), and 10-30% of individuals with LN progress to end-stage kidney disease (kidney failure). Despite advances in monitoring and treatment, only about half of patients achieve remission (kidney improvement), and LN is one of the leading causes of death in SLE. Fibroblasts are cells that respond to kidney damage in lupus nephritis to heal wounds and repair the tissue. When this process goes awry, excessive fibroblast activation causes fibrosis–scar tissue formation that impacts kidney function. Recent data show that various features of fibrosis strongly predict poor outcomes like kidney failure and death in LN. A protein produced by some fibroblasts called S100A4 is higher than normal in the kidneys of people with other chronic kidney diseases and has been shown to drive damage to many tissues, including the skin, lungs, heart, and liver, but S100A4 has not yet been studied in LN. Because of the disease-causing role of S100A4 and the benefits of blocking S100A4 in other kidney disease models, Dr. Mohan will explore the role of S100A4 in LN to test whether blocking S100A4 lessens kidney fibrosis in LN.

Dr. Mohan recently found that S100A4 is higher than normal in the kidneys and urine of people with LN. To determine whether S100A4 drives fibrosis in LN, Dr. Mohan will first characterize the levels and location of S100A4 in human kidney samples and mouse models of LN, with the prediction that increased S100A4 levels are associated with more severe disease. The team will then use genetic tools or drugs to target S100A4 in a mouse model of LN to determine the potential of blocking S100A4 as a treatment for LN. Lastly, Dr. Mohan will assess if the level of S100A4 in kidney biopsy samples can be used to predict treatment response and long-term outcomes.

What this study means for people with lupus

S100A4 is a novel, druggable target not yet studied in LN, and the outcomes of this study could lead to testing the effectiveness of blocking S100A4 in human LN trials. Determining if S100A4 levels can predict a person’s response to treatment and/or long-term outcomes could help spot people with LN who would benefit from clinical trials or those who need more aggressive intervention and monitoring.

End-stage kidney disease requiring dialysis or transplant is a major cause of morbidity and mortality in patients with lupus. Multiple studies have revealed that fibrotic changes in renal pathology portend poor patient outcome and renal survival in patients with lupus nephritis (LN). Thus, elucidating the drivers of renal fibrosis is of utmost importance in LN. A key determinant of renal fibrosis is a cell called the fibroblast, marked by expression of a protein called S100A4. a poorly studied cell in LN. Studies in other fibrotic diseases have clearly shown that S100A4 is not just a marker of fibroblasts and pro-fibrosis, it is a pathogenic driver of fibrosis, acting via multiple pathways. Most importantly, blocking S100A4 in other fibrotic diseases is highly effective. Our recent preliminary data indicate that S100A4 is also elevated in LN kidneys, in association with disease:

1. S100A4 is elevated in LN kidneys particularly in patients with high renal pathology disease with fibrotic changes.
2. Based on 50-plex staining for multiple target proteins, the predominant cell in LN expressing S100A4 were macrophages and fibroblasts.
3. S100A4 is also elevated at the RNA level in LN kidneys, corroborating our findings at the protein level. 4. Urinary S100A4 is also elevated in patients with active renal lupus compared to controls.
4. Intra-renal S100A4 was also elevated in murine lupus, in two different strains.

Based on literature reports and our preliminary findings, we hypothesize that S100A4 is an essential driver of renal fibrosis in LN that can be therapeutically targeted. Unlike other targets in LN, S100A4 is particularly attractive in LN for many reasons: Blocking other proteins important in fibrosis is not feasible. Blocking TGF-?, though feasible, will not be useful as this cytokine plays opposing roles in LN, suppressing systemic disease but worsening renal pathology. In this context, S100A4 blockade appears attractive as it is hyper expressed in LN kidneys, but not in peripheral blood.

Three Aims are proposed to test the above hypothesis:

Aim 1: To characterize the expression profile of S100A4 in human and murine LN, as a function of disease

Aim 2: To ascertain the pathogenic relevance and therapeutic potential of S100A4, using mouse LN models

Aim 3: To assess if renal S100A4 expression is a predictor of treatment response or long-term outcome in LN Since renal fibrosis is a leading cause of morbidity and mortality in patients with lupus, and since the protein called S100A4 is a central driver of renal fibrosis, blocking S100A4 is predicted to ameliorate lupus nephritis and improve long term outcome.

Moreover, none of the currently approved/used drugs in LN target renal fibrosis. Since blocking S100A4 has already been shown to be therapeutic in other renal diseases, the proposed therapeutic approach is likely to have a significant impact on reducing morbidity and mortality in patients with lupus.