Abstract
In aging kidneys a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological". Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by high salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as key orchestrator of organ fibrosis to the observed differences is determined by comparison to a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal (NSD, standard chow) or high salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 months revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring (PAS, Masson's trichrome, Sirius red staining) prevails. In Ybx1ΔRosaERT+TXanimals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TXanimals. In vitro Ybx1ΔRosaERT+TXbone marrow derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TXanimals.
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