Glomerular common gamma chain confers B- and T-cell-independent protection against glomerulonephritis.

Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell-independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice (Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/-) that are devoid of either T/B cells or T/B/NK cells. The Rag2-/-Il2rg-/- or Rag2-/-Il2rb-/- mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor ß subunit (IL-2Rß), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice (Rag2-/-Il2rg-/- and Rag2-/-Il2rb-/-) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15-dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rß. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rß receptor response, to date classically described only in immune cells.

Genetic background-dependent thrombotic microangiopathy is related to vascular endothelial growth factor receptor 2 signaling during anti-glomerular basement membrane glomerulonephritis in mice.

Because genetic background plays a pivotal role in humans and in various experimental models, we carefully monitored its impact on glomerular pathological characteristics during experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN), using two leading mouse strains, 129S2/SvPas (129Sv) and C57bl/6J (B6J). These mice exhibited different severities of renal failure, hypertension, and glomerular lesions, according to their genetic background. In addition to the classic glomerular proliferative lesions, glomerular thrombotic microangiopathy (TMA) was found as a common genetic background-dependent histopathological hallmark of anti-GBM-GN, combined with hemolytic anemia and thrombocytopenia. Glomerular expression profiling, using microarrays and Western blot analysis in B6J TMA-resistant and 129Sv TMA-prone mice, demonstrated major differences in vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) 2 pathways, despite similar Vegfa expression levels. Further analysis revealed a lower basal glomerular endothelial Vegfr2 expression level in 129Sv TMA-prone mice compared with B6J TMA-resistant mice. This difference was even more pronounced during anti-GBM-GN, explaining why an exogenous VEGFA supply failed to rescue any 129Sv TMA lesions. Conversely, the systemic blocking of Vegfr2 amplified TMA lesions only in B6J mice. Herein, we specified the role that genetic background plays in determining, in particular, the level of Vegfr2 expression. We also demonstrated that glomerular Vegfr2-dependent TMA lesions are an underevaluated common hallmark of anti-GBM-GN in mice.