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Immune cells and compensatory renal hypertrophy after unilateral nephrectomy

ABSTRACT: Background: The underlying mechanisms of compensatory renal hypertrophy (CRH) after unilateral nephrectomy (UNX) are complex and incompletely understood. Most studies have examined hemodynamic and tubular epithelial factors. We studied immune cells in CRH after UNx in mice. Methods: Following UNx of the left kidney of C57BL/6J WT mice, GFR measurements, flow cytometry, single-cell RNA sequencing, and measurements of remnant kidney were performed over 8-weeks period. Rag1-/- mice lacking T and B cells were studied to begin to study the role of direct role of adaptive immune cells in CRH. Results: The largest increase in GFR and increase in kidney weight-to-body weight ratio (KW:BW) in WT mice was at 24 hours, after which GFR remained relatively constant while KW:BW steadily increased. Immune cell populations exhibited dynamic and time-dependent fluctuations following UNx. Early responses (4 and 72 hours) were characterized by significant changes in CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. Later time points (1 to 8 weeks) showed increased effector memory T cells and B cells, with decline in naïve T cells and macrophages. GFR was significantly higher at 1 week and 4 weeks in Rag1-/- mice compared to controls. Conclusions: Immune cells undergo significant changes in numbers, phenotype and transcriptional programming during CRH after UNx, and could have a direct role in modifying GFR adaptations.

ORGANISM(S): Mus musculus

PROVIDER: GSE300404 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Background: Several studies suggest that dietary beta hydroxybutyrate supplementation delays the progression of chronic kidney disease (CKD) by suppressing inflammation and fibrosis. We hypothesized that the oral supplementation with the beta-hydroxybutyrate (BHB) precursor 1,3-butanediol in addition to inhibitors of the renin-angiotensin system (RAS) and sodium-glucose transporter (SGLT)2 would be superior to dual RAS/SGLT2 blockade alone in attenuating the loss of glomerular filtration rate in Col4a3-deficient mice with Alport nephropathy, a spontaneous model of progressive CKD. Methods: We performed a placebo-controlled study in Col4a3-deficient mice with Alport nephropathy. Treatment was initiated at a late stage of the disease at the age of six weeks. Mice were fed food admixes of 10 μg/g ramipril plus 30 μg/g empagliflozin with or without addition of 0,04g/g 1,3-butanediol (concentration per gram of bodyweight). The mice were monitored daily and sacrificed upon reaching renal failure. The glomerular filtration rate (GFR) was measured at the start of the treatment and after one and four weeks. Results: The addition of beta hydroxybutyrate significantly attenuated the loss of glomerular filtration rate beyond the effect of dual RAS/SGLT2 blockade. The mean glomerular filtration rate after four weeks of treatment was 1.4±5.0 μl/min (vehicle), 61.3±51.1 μl/min (RASi + SGLT2i), and 138.9±68.5 μl/min (RASi + SGLT2i + 1,3-butanediol). No additional effects on lifespan could be observed. Kidney RNA sequencing revealed significant protective effects on inflammation when adding the beta hydroxybutyrate precursor 1,3-butanediol to RAS/SGLT2 inhibition. In histopathology, antifibrotic effects were seen upon beta hydroxybutyrate addition. Conclusion: The results in mice suggest that beta hydroxybutyrate supplementation improves the GFR in Alport syndrome by suppressing inflammation and fibrosis. However, the effects did not lead to a significant increase in lifespan. Furthermore, the observed effects stay behind the effects of finerenone as a combination partner, which was tested earlier in the same mouse model.

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Immune cells and compensatory renal hypertrophy after unilateral nephrectomy

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