No abstract

Lymphangiogenesis is associated with chronic kidney disease (CKD) and occurs following kidney transplant. Here, we demonstrate that expanding lymphatic vessels (LVs) in kidneys and corresponding renal draining lymph nodes (RDLNs) play critical roles in promoting intrarenal inflammation and fibrosis following renal injury. Our studies show that lymphangiogenesis in the kidney and RDLN is driven by proliferation of preexisting lymphatic endothelium expressing the essential C-C chemokine ligand 21 (CCL21). New injury-induced LVs also express CCL21, stimulating recruitment of more CCR7+ dendritic cells (DCs) and lymphocytes into both RDLNs and spleen, resulting in a systemic lymphocyte expansion. Injury-induced intrarenal inflammation and fibrosis could be attenuated by blocking the recruitment of CCR7+ cells into RDLN and spleen or inhibiting lymphangiogenesis. Elucidating the role of lymphangiogenesis in promoting intrarenal inflammation and fibrosis provides a key insight that can facilitate the development of novel therapeutic strategies to prevent progression of CKD-associated fibrosis.

Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro, but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.