Role of TNF-α on progressive glomerulosclerosis in Alport nephropathy

The pathomechanisms of the progression of chronic kidney diseases
involve progressive glomerulosclerosis with renal parenchymal cell
loss by proapoptotic factors. Tumor necrosis factor-alpha (TNF-α)
is a proapoptotic cytokine that is produced by macrophages as well
as by a variety of cell types. TNF-α signaling regulates cell
survival and death. Like in other inflammatory renal diseases, the
increased intrarenal TNF-α expression contributes to the disease
progression of Alport nephropathy, “a non-inflammatory” murine CKD
model. I show that TNF-α expressed by podocytes as well as by
infiltrating leukocytes progressively activates renal parenchymal
cells, inducing apoptotic pathways that can trigger
glomerulosclerosis in Alport disease. The blockade of TNF-α by
etanercept prolonged mean survival of Col4a3-deficient mice. The
beneficial effect on life span was associated with a significant
improvement of the glomerulosclerosis, proteinuria, and the
glomerular filtration rate (GFR). In particular, etanercept
treatment significantly increased the number of glomerular
podocytes (WT-1 and nephrin co-staining) and the renal mRNA
expression of nephrin and podocin without affecting markers of
renal inflammation. The increased number of podocytes was
consistent with less TUNEL-positive podocytes that undergo
apoptosis. Importantly, exogenous signals, e.g. infections or
toxins, have the potential to regulate the influx of immune cells
including dendritic cells, macrophages, neutrophils, and T cells.
Here I report a large influx of leukocyte subsets that are mostly
dendritic cells and macrophages in Col4a3-deficient mice as
compared to wildtype mice. While bacterial endotoxin treatment had
no effect on the renal disease progression, bacterial
cytosine-guanine (CpG)-DNA exacerbated all aspects of Alport
nephropathy and reduced the overall life span of Col4a3-deficient
mice. This effect of CpG-DNA was associated with a significant
increase of renal CD11b+/Ly6Chigh macrophages, intrarenal
production of TNF-α, iNOS, IL-12, and CXCL10. CpG-DNA switched
intrarenal macrophages from non-activated phenotype (M2) towards
the classically activated form (M1). These M1 macrophages increased
the secretion of TNF-α, which accelerated the disease progression
of Alport nephropathy by inducing podocyte loss. Taken together, I
demonstrated that TNF-α is a crucial cytokine which induces
podocyte loss in the natural course of the progression of Alport
nephropathy. Moreover, the expression of TNF-α is enhanced by
selective exogenous factors, e.g. TLR9 activation, which alter the
phenotype of renal macrophages towards the M1 phenotype. TNF-α
blockade might therefore represent a novel therapeutical option to
delay the progression of Alport nephropathy and potentially of
other forms of glomerulosclerosis in non-inflammatory and
inflammatory conditions.