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Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.

Abstract Background Left ventricular hypertrophy (LVH) increases the risk of death in chronic kidney disease (CKD). The transcription factor Kruppel-like factor 15 (KLF15) is expressed in the heart and regulates cardiac remodelling through inhibition of hypertrophy and fibrosis. It is unknown if KLF15 expression is changed in CKD induced LVH, or whether expression is modulated by blood pressure reduction using angiotensin converting enzyme (ACE) inhibition. Methods CKD was induced in Sprague–Dawley rats by subtotal nephrectomy (STNx), and rats received vehicle (n = 10) or ACE inhibition (ramipril, 1 mg/kg/day, n = 10) for 4 weeks. Control, sham-operated rats (n = 9) received vehicle. Cardiac structure and function and expression of KLF15 were assessed. Results STNx caused impaired kidney function (P

Abstract Background The pathological condition of chronic kidney disease may not be adequately recapitulated in immunocompromised mice due to the lack of T-cells, which are important for the development of hypertension and renal injury. We studied the role of the immune system in relation to salt-sensitive hypertension and renal injury in mice with subtotal nephrectomy (SNX). Methods Wild-type immunocompetent (WT) and Foxn1nu/nu athymic immunodeficient (AT) CD-1 mice underwent SNX to induce renal injury after which they received standard chow or a high salt diet (HSD). Four weeks after SNX blood pressure and kidney function parameters were measured. Results HSD increased albumin excretion independent of immune status. Systolic blood pressure increased only in WT mice on HSD, not in AT mice. Uremia and morphological damage after SNX were not affected by either HSD or immune status. Conclusions For the development of hypertension after SNX in CD-1 mice mature T-cells and a high salt diet are required. SNX induced albuminuria was independent of the presence of T-cells.

Advanced glycation end products (AGEs) contribute to the pathogenesis of renal diseases and have become a new therapeutic target for treatment. Chronic renal failure (CRF) is the end-stage of chronic renal diseases and highly associated with increased incidence in cardiovascular complications, however, some of the pathogenesis has not yet been fully clarified. This study was designed to evaluate the therapeutic or preventive potential of pyridoxamine (PM) against CRF in a 5/6 subtotal nephrectomy rat model. Significant and beneficial contributions to body weight, cardiovascular parameters, clearances of creatinine and BUN and AGEs reduction were observed in CRF rats receiving PM for 8 weeks. PM supplementation might be considered as one of pharmacological strategies for preventing AGE-related pathologies and early stages of renal damage. Prospective trials are needed to elucidate a potential role for PM in adjunctive therapy and to confirm the adequate amount on cardiovascular and renal outcomes in CRF.

Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP). Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT) and P2Y2 receptor knockout (KO) mice.During the observational period of 56 ± 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9±7.7 vs. 84.3±8.7µl/min at day 56). The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177±2 vs. 156±7 mmHg) and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-β1, PAI-1) and proinflammatory target genes (MCP1) were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease.