Background and Purpose: Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia–reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI.Experimental Approach: IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg⁻¹·day⁻¹), vildagliptin (8 mg·kg⁻¹·day⁻¹) and sitagliptin (30 mg·kg⁻¹·day⁻¹). An additional group received sitagliptin until study end (before IRI: 30 mg·kg⁻¹·day⁻¹; after IRI: 15 mg·kg⁻¹·day⁻¹).Key Results: Plasma‐active glucagon‐like peptide type 1 (GLP‐1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug‐specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI‐related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose‐adjusted sitagliptin group. Active GLP‐1 plasma levels at study end were increased only in the prolonged/dose‐adjusted sitagliptin treatment group.Conclusions and Implications: In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.

Background: Vitamin D is a fat-soluble steroid that influences cardiovascular health by affecting lipid metabolism. Since dyslipidemia is a key risk factor for cardiovascular disease (CVD), our study aimed to explore the relationship between vitamin D levels and lipid parameters, considering the effects of age and gender. Methods: In this cross-sectional study of 47,778 outpatients, we analyzed correlations between two forms of vitamin D—25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)₂D)—and lipid parameters, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol (TC). Subgroup analyses by age and gender provided additional insights. Results: Results showed that 25(OH)D levels were negatively correlated with LDL and TC across the cohort. This association was particularly evident in men over 50, whereas women showed a positive correlation with LDL and TC before age 50 and a negative correlation after. HDL levels positively correlated with 25(OH)D across all age groups, with the strongest association in postmenopausal women. In contrast, 1,25(OH)₂D showed a positive correlation only with HDL in individuals over 50, with no significant correlation with LDL or TC in any age group. Conclusions: In conclusion, findings from this cross-sectional study underscore an association between elevated levels of 25(OH)D and more favorable lipid profiles, characterized by reduced LDL and total cholesterol, as well as increased HDL levels. This association is particularly pronounced among individuals over 50 years of age and postmenopausal women.

Target values for 25-hydroxy vitamin D and 1,25(OH)₂D or 1,25-dihydroxy vitamin D remain a topic of debate among clinicians. We analysed data collected from December 2012 to April 2020 from two cohorts. Cohort A, comprising 455,062 subjects, was used to investigate the relationship between inflammatory indicators (white blood cell [WBC] count and C-reactive protein [CRP]) and 25(OH)D/1,25(OH)₂D. Cohort B, including 47,778 subjects, was used to investigate the connection between 25(OH)D/1,25(OH)₂D and mineral metabolism markers (phosphate, calcium, and intact parathyroid hormone [iPTH]). Quadratic models fit best for all tested correlations, revealing U-shaped relationships between inflammatory indicators and 25(OH)D and 1,25(OH)₂D. Minimal CRP and WBC counts were observed at 1,25(OH)₂D levels of 60 pg/mL and at 25(OH)D levels of 32 ng/mL, as well as of 42 ng/mL, respectively. iPTH correlated inversely with both 1,25(OH)₂D and 25(OH)D, while phosphate as well as calcium levels positively correlated with both vitamin D forms. Calcium-phosphate product increased sharply when 25(OH)D was more than 50 ng/mL, indicating a possible risk for vascular calcification. Multiple regression analyses confirmed that these correlations were independent of confounders. This study suggests target values for 25(OH)D between 30–50 ng/mL and for 1,25(OH)₂D between 50–70 pg/mL, based particularly on their associations with inflammation but also with mineral metabolism markers. These findings contribute to the ongoing discussion around ideal levels of vitamin D but require support from independent studies with data on clinical endpoints.

Preclinical work indicates that calcitriol restores vascular function by normalizing the endothelial expression of cyclooxygenase-2 and thromboxane-prostanoid receptors in conditions of estrogen deficiency and thus prevents the thromboxane-prostanoid receptor activation-induced inhibition of nitric oxide synthase. Since endothelial dysfunction is a key factor in the pathogenesis of cardiovascular diseases, this finding may have an important translational impact. It provides a clear rationale to use endothelial function in clinical trials aiming to find the optimal dose of vitamin D for the prevention of cardiovascular events in postmenopausal women.

Left ventricular hypertrophy (LVH) is a common cardiac complication in patients with cardiorenal syndrome. Empagliflozin has demonstrated cardio-renal protective effects in clinical studies, potentially linked to reductions in left ventricular mass (LVM). Using a 5/6 nephrectomy rat model to induce cardiorenal syndrome, we administered two doses of Empagliflozin (3 mg/kg/day and 15 mg/kg/day) via gavage for 95 days, with Telmisartan as a positive control. Cardiac structure and function were assessed using echocardiography, histological analysis, and serum biomarkers. Single-nucleus RNA sequencing (snRNA-seq) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to investigate molecular mechanisms. The 5/6 nephrectomy increased serum creatinine, troponin T, LVM, ejection fraction, and cardiomyocyte diameter. Empagliflozin treatment significantly decreased LVM and cardiomyocyte hypertrophy, comparable to Telmisartan. snRNA-seq revealed no changes in major cardiac cell populations but identified differential expression of cardiomyocyte development genes, including Fhl2, Tbx20, and Angpt1. qRT-PCR data for Fhl2 and Tbx20 aligned with the snRNA-seq data, showing that Empagliflozin increased Fhl2 expression and decreased Tbx20 expression. Immunofluorescence showed increased myocardial infiltration of M2 macrophages, CD4 + T cells, and CD8 + T cells in Empagliflozin-treated rats, but there was no difference between the 5/6 nephrectomized rats and normal rats. In a non-diabetic cardiorenal syndrome model, Empagliflozin effectively attenuated left ventricular hypertrophy and cardiomyocyte enlargement. These effects appear mediated by the regulation of genes involved in cardiomyocyte development and myocardial remodeling (Fhl2 and Tbx20), rather than cardiomyocyte proliferation. These findings highlight Empagliflozin's cardioprotective potential in cardiorenal syndrome and provide a foundation for further clinical exploration.