Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19 Ludwig-Maximilians-Universität München

The global burden of chronic kidney diseases remains an ongoing medical challenge.
Therapies that can halt or reverse advanced renal injury are not yet available. Increasing
numbers of patients progress to the end-stage renal failure and require renal replacement
therapy, the latter being associated with significant mortality, a lower quality of life, and high
costs for national health systems. Thus, new treatment strategies that slow down, halt or even
revert progressive renal damage are requested.
Chemokines and their receptors are involved in the pathogenesis of renal diseases. They
mediate leukocytes and macrophages recruitment and activation during initiation as well as
progression of renal inflammation. Infiltrating leukocytes are the major source for
proinflammatory and profibrotic cytokines and are therefore critical for mediating fibroblast
proliferation, differentiation into myofibroblasts, matrix production, and tubular atrophy.
Recent advances in the understanding of the molecular mechanisms that regulate renal
leukocyte recruitment suggest chemokines and chemokine receptors as novel targets for
specific pharmacological intervention.
The aim of the present thesis was to investigate the role of chemokine receptor CCR1 for the
progression of chronic kidney diseases, e.g. Alport disease and diabetic nephropathy. Two
different animal models were used: Col4A3-deficient mice and type 2 diabetic db/db mice
with advanced diabetic nephropathy. We blocked CCR1 in Col4A3-deficient mice with
BX417, a small molecule CCR1 antagonist, and BL5923, a novel orally available antagonist
with a high specificity for human and murine CCR1 in uninephrectomized type 2 diabetic
db/db mice, respectively.
Treatment with BX471 (25mg/kg) from weeks 6 to 10 of life improved survival of COL4A3-
deficient mice, characterized by glomerulosclerosis and subsequent progressive
tubulointerstitial injury, leading to fatal end-stage renal disease (ESRD). Improvement was
associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular
atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal
Ccl5 mRNA expression by reducing the number of interstitial CCL5-positive cells in
inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice
identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular
endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and
interstitial migration were not affected. Furthermore, in activated murine macrophages,
BX471 completely blocked CCL3-induced CCL5 production.
When CCR1 was blocked with BL5923 (60mg/kg, b.i.d), the interstitial recruitment of ex
vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice
with type 2 diabetes. Similarly, BL5923 orally administered from month 5 to 6 of life
reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was
associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial
cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular
pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal
mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, Tgf-β1, and collagen I-α1 when compared to
untreated uninephrectomized male db/db mice of the same age.
Thus, we identified a previously unrecognized role for CCR1-dependent recruitment of
interstitial macrophages for the progression of chronic kidney disease in Alport disease and
diabetic nephropathy. These data identify CCR1 as a potential therapeutic target for Alport
disease and late stage diabetic nephropathy or other progressive nephropathies associated
with interstitial macrophage infiltrates.

Es werden die Aufgaben und Tätigkeitsbereiche der Ärztlichen Stellen beschrieben und die Arbeitsweise der Ärztlichen Stelle der Bundeswehr mit einer Auswertung der durchgeführten Prüfungen dargestellt.