Ex vivo exposure of bone marrow from chronic kidney disease donor rats to pravastatin limits renal damage in recipient rats with chronic kidney disease

Abstract

IntroductionHealthy bone marrow cell (BMC) infusion improves renal function and limits renal injury in a model of chronic kidney disease (CKD) in rats. However, BMCs derived from rats with CKD fail to retain beneficial effects, demonstrating limited therapeutic efficacy. Statins have been reported to improve cellular repair mechanisms.MethodsWe studied whether exposing CKD rat BMCs ex vivo to pravastatin improved their in vivo therapeutic efficacy in CKD and compared this to systemic in vivo treatment. Six weeks after CKD induction, healthy BMCs, healthy pravastatin-pretreated BMCs, CKD BMCs or CKD pravastatin-pretreated BMCs were injected into the renal artery of CKD rats.ResultsAt 6 weeks after BMC injection renal injury was reduced in pravastatin-pretreated CKD BMC recipients vs. CKD BMC recipients. Effective renal plasma flow was lower and filtration fraction was higher in CKD BMC recipients compared to all groups whereas there was no difference between pravastatin-pretreated CKD BMC and healthy BMC recipients. Mean arterial pressure was higher in CKD BMC recipients compared to all other groups. In contrast, 6 weeks of systemic in vivo pravastatin treatment had no effect. In vitro results showed improved migration, decreased apoptosis and lower excretion of pro-inflammatory Chemokine (C-X-C Motif) Ligand 5 in pravastatin-pretreated CKD BMCs.ConclusionsShort ex vivo exposure of CKD BMC to pravastatin improves CKD BMC function and their subsequent therapeutic efficacy in a CKD setting, whereas systemic statin treatment did not provide renal protection.

A perspective on chronic kidney disease progression

“…Several other drugs also affect EPCs, including erythropoietin-stimulating agents, calcium channel blockers, biguanides without or with thiazolidinedione, and dipeptidyl peptidase-4 inhibitors (49). Drugs, such as pravastatin, rosiglitazone, or coenzyme Q10, improve function and reduce senescence or apoptosis in MSCs (5,90). Last, both EPCs and MSCs release microparticles, which carry genetic and protein cargo.…”

Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease

“…Autologous therapy should thus be considered for these patients-provided that disease-induced dysfunction is not present. Preclinical studies show a pronounced reduction in vascular regenerative effects of BM mononuclear cells of donors with cardiovascular disease (CVD), including CKD [16]. In culture-expanded MSCs, the effect of CVD is less clear, with conflicting reports depending on the cardiovascular disease (model) and little information available for CKD [17].…”

“…There were preliminary indications that the paracrine function might not be preserved in CKD. Progenitor cells in experimental CKD display an altered paracrine profile, including reduced expression of vascular endothelial growth factor (VEGF) and reduced migration towards chemotactic stimuli [16,36]. Furthermore, in vitro studies have shown that a uremic environment negatively affects progenitor cell function [37,38].…”

Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

“…Drugs or interventions that may improve function and reduce senescence or apoptosis in MSC include hypoxic and other preconditioning measures 166–168 , pravastatin 169 , rosiglitazone 170, 171 or coenzyme Q10 172 therapies, and epigenetic regulation 173, 174 . Both preconditioned MSC and EPC have shown improved cell survival, homing to injured sites, and paracrine activities.…”