The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis

Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment

Background: Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. Methods: Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. Results: A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. Conclusions: There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD

Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid-base balance

BACKGROUND: Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy is associated with altered expression of proteins involved in renal acid-base metabolism. METHODS: We collected retrospectively kidney biopsies from 22 patients. Of these patients, 9 had no acidosis, 9 had metabolic acidosis (plasma HCO3- < 22 mmol/l), and 4 had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling. RESULTS: We found the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule amino acid and lipid metabolism and energy homeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 K+-channel, an important regulator of proximal tubule HCO3--metabolism and transport, ACADSB and SHMT1, genes involved in beta-oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the proximal tubule NBCe1 HCO3- transporter in kidneys from acidotic patients that recovered with alkali therapy. In addition, the HCO3-exchanger pendrin was affected by acidosis and alkali therapy. CONCLUSIONS: Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from proximal tubule were also affected by acidosis and alkali therapy suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients