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Gut alterations in a chronic kidney disease rat model with diet-induced vascular calcification
Piotr Bartochowski1,2, Irene Cortijo1, Shruti Bhargava3
1RD Néphrologie SAS, Montpellier, France.
Insights
Vascular calcification in chronic kidney disease (CKD) is linked to reduced gut mucus production, potentially worsening uremic toxin buildup. Enhancing the gut mucus barrier may offer a therapeutic strategy for CKD patients.
Area of Science:
- Nephrology
- Gastroenterology
- Pathology
Background:
- Chronic kidney disease (CKD) is frequently associated with intestinal disorders and vascular calcification (VC).
- Gut barrier alterations like increased permeability and inflammation are known in CKD, but the influence of VC on these changes is unclear.
- Uremic toxins and inflammation are suspected mediators of the relationship between VC and gut dysfunction.
Purpose of the Study:
- To investigate the bidirectional relationship between vascular calcification and gut dysfunction in a rat model of chronic kidney disease.
- To determine if inflammation and uremic toxin generation mediate the link between VC and gut alterations.
- To explore the role of mucus production and NLRP6 inflammasome in this context.
Main Methods:
- Utilized a subtotal 5/6th nephrectomy (SNx) rat model with a pro-calcifying diet to induce uremic vascular calcification (SNx-VC).
- Assessed CKD and VC using von Kossa staining.
- Measured gut barrier integrity, mucus production (Alcian blue, Mucin 2), inflammation markers, tight junction proteins, and gene/protein expression of NLRP6, Ly96, Sod1, and Tlr2.
Main Results:
- SNx-VC rats exhibited confirmed CKD and VC, with elevated levels of the gut-origin uremic toxin indoxyl sulfate (IS).
- A significant decrease in colonic and ileal mucus production was observed, correlating with the severity of vascular calcification.
- While inflammation and tight junction proteins remained unchanged, Nlrp6 mRNA levels decreased in the colon of SNx-VC rats, alongside altered expression of other inflammatory-related genes.
Conclusions:
- A strong link exists between reduced gut mucus production, decreased Nlrp6 mRNA, elevated indoxyl sulfate, and uremic vascular calcification in CKD.
- Alterations in the gut mucus layer may promote the generation of uremic toxins, thereby exacerbating vascular calcification in CKD.
- Improving gut mucus barrier function presents a potential therapeutic avenue for managing uremic VC in CKD patients.
Abstract:
Intestinal disorders and vascular calcification (VC) are often associated with chronic kidney disease (CKD). While gut barrier alterations have been reported in CKD (such as abnormal intestinal permeability, bacterial overgrowth, and inflammation), it is not clear if vascular calcification influences these alterations. To investigate whether the bidirectional relationships between VC and gut dysfunction could be mediated by increased inflammation and uremic toxin generation, we used the SNx-VC model of uremic vascular calcification (rats undergoing subtotal 5/6th nephrectomy and fed a procalcifying high-phosphate and vitamin D diet). We confirmed the presence of CKD and VC by von Kossa staining and observed increased gut-origin uremic toxin, indoxyl sulfate (IS), in SNx-VC animals compared to controls. In SNx-VC rats, we observed decreased mucus production (Alcian blue, Mucin 2 staining) in the colon and ileum which was correlated with the level of calcification. There was no change in inflammation markers or tight junction protein expression. We assessed intestinal levels in the NOD-like receptor family pyrin domain containing 6 (NLRP6) protein, known to regulate mucus secretion, and found no change in the colon or ileum. Nlrp6 mRNA was, however, decreased in the colon of SNx-VC rats, along with other mRNA (Ly96, Sod1), while Tlr2 was increased compared to controls. Our observations of low mucus, low Nlrp6 mRNA, and high IS in SNx-VC rats confirm a link between gut barrier alterations and uremic VC. This suggests that alterations in the mucus layer could favor the generation of gut-origin uremic toxins and promote VC in CKD. Thus, improving the gut mucus barrier function in the context of uremic VC could be considered as a possible therapeutic strategy in CKD patients.
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