The switch we identified is a protein called Ptprz that is made by kidney cells and immune cells. To reveal Ptprz’s role in kidney inflammation, we will study genetically modified, lupus-prone mice that lack the protein to find out if they have less inflammation. We will also give other lupus-prone mice a drug developed to treat brain cancer that blocks Ptprz. To find out whether Ptprz is important in lupus, we will analyze kidney tissue from patients with the disease and ask if people with more severe kidney damage produce more Ptprz.

What this study means to people with lupus

“We may have discovered a master switch that turns on kidney inflammation, which affects about half of patients with lupus. Our study will determine whether eliminating this switch or shutting it off protects the kidneys in mice. Our results could lead to clinical trials of drugs that turn off the switch.”

Nephritis is the major cause of mortality and morbidity in patients with lupus. The magnitude of inflammation and fibrosis in the renal tubulo-interstitium is the most accurate predictor of clinical outcomes in chronic kidney disease lupus nephritis (LN). Macrophages recruited into the kidney interacting with, tubule epithelial cells (TEC) drive inflammation and fibrosis in LN. Our prior findings show that genetically deleting a principle molecule (IL-34) required for macrophage survival and proliferation, suppresses LN in mice. IL-34 has a newly identified second receptor, Protein-Tyrosine Phosphatase Receptor zeta (Ptprz). Notably multiple Ptprz lligands, other than IL-34, including midkine [Mdk], tenacin C [Tnc], and pleiotrophin [Ptn]) are implicated in inflammation and fibrosis, and are elevated in the serum of patients with lupus. We discovered the novel finding that TEC and leukocytes (macrophages, T and B cells), express Ptprz. Macrophages, T and B cells are pivotal in LN and multiple Ptprz ligands are implicated in lupus. Thus, Ptprz may be a “master switch” for LN. Our preliminary data indicates that: (i) intra-renal Ptprz and Ptprz ligands (IL-34, Mdk, Tnc, and Ptn) are increased in MRL-Faslpr and NZB/W mice with LN; (ii) ischemia/reperfusion injury (I/R) incited CKD (including loss of renal function, tubule destruction, interstitial inflammation and fibrosis) is suppressed in Ptprz null mice; (iii) intra-renal Ptprz and Ptprz ligands are expressed in patients with LN, and not normal volunteers; and (iv) Ptprz is similarly expressed by TEC and leukocytes (macrophages/monocytes, T and B cells) in mice and patients with lupus. We propose to test the hypothesis that Ptprz?is a promising therapeutic target for LN. The specific aims are: (1) Test the hypothesis that genetically deleting (proof of concept), and pharmacologically inhibiting (pre-clinical approach) Ptprz suppresses LN in MRL-Faslpr mice. We will pinpoint the time during which Ptprz requires inhibition to maximally suppress the progression of LN in multiple lupus-prone strains. (2) Test the hypothesis that Ptprz promotes LN in patients (human translation). Using LN patients in comparison to relevant controls we will determine whether: A. Intra-renal Ptprz expression correlates with the histopathologic severity of LN; and B. Ptprz expressing circulating leukocytes (monocytes, T and B cells) track with LN disease activity. (3) Test the hypothesis that intra-renal Ptprz and Ptprz-ligand dependent interactions foster inflammation and fibrosis. Using TEC and macrophages (mouse and human) expressing Ptprz, we will determine whether Ptprz and select Ptprz ligand interactions: (i) fuel inflammation and (ii) promote kidney precursor fibroblast differentiation. Collectively, our findings will potentially guide the design and prompt clinical trials to determine whether Ptprz is a therapeutic target for patients with LN.