Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.

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 a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals 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+TX animals. In vitro Ybx1ΔRosaERT+TX bone 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+TX animals.NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.

• Authors: Anja Bernhardt, Anna Krause, Charlotte Reichardt, Hannes Steffen, Berend Isermann, Uwe Völker, Elke Hammer, Robert Geffers, Lars Philipsen, Kristin Dhjamandi, Sohail Ahmad, Sabine Brandt, Jonathan A Lindquist, Peter R Mertens
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 325 Issue 2 Pg. C456-C470 (08 01 2023) ISSN: 1522-1563 [Electronic] United States
• PMID: 37399499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sodium Chloride
• Sodium Chloride, Dietary

Topics

• Mice
• Animals
• Sodium Chloride
• Kidney (metabolism)
• Kidney Diseases (chemically induced, genetics, pathology)
• Inflammation (metabolism)
• Aging
• Hypertension (metabolism)
• Sodium Chloride, Dietary (adverse effects)
• Fibrosis
• Eating