Bone marrow mononuclear cells shift bioactive lipid pattern in injured kidney towards tissue repair in rats with unilateral ureteral obstruction

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2010-12, Vol.25 (12), p.3867-3874
• Main Authors: Verdoorn, Karine S., Lindoso, Rafael S., Lowe, Jennifer, Lara, Lucienne S., Vieyra, Adalberto, Einicker-Lamas, Marcelo
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Acute Kidney Injury - physiopathology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; bioactive lipids; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - physiology; Bone Marrow Transplantation; Calcium-Transporting ATPases - metabolism; Cell Proliferation; Cell Survival; cell therapy; Diglycerides - metabolism; Emergency and intensive care: renal failure. Dialysis management; Intensive care medicine; kidney; Kidney - pathology; Kidney - physiology; Lipids - physiology; Male; Medical sciences; Models, Animal; Rats; Rats, Wistar; Receptors, Lysophosphatidic Acid - metabolism; Regeneration - physiology; Signal Transduction - physiology; Sphingolipids - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; tissue repair; unilateral ureteral obstruction; Ureteral Obstruction - complications; Ureteral Obstruction - metabolism; Ureteral Obstruction - physiopathology
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfq286

Background. Bioactive lipids are important in tissue injury and regeneration. Ceramide (Cer) is known for its pro-apoptotic action and sphingosine-1-phosphate (S1P) for inducing proliferation and cell survival; diacylglycerol (DAG) and lysophosphatidic acid (LPA) are involved in various signalling pathways including modulation of ion transport. LPA signalling through its receptor LPA1 is also related to the progression of fibrosis. This study investigated the modulation of lipid signalling pathways induced by administration of bone marrow-derived mononuclear cells (BMMC) in chronic kidney disease. Methods. Unilateral ureteral obstruction (UUO) was followed by intravenous injection of ∼2×107 BMMC. Controls were UUO group treated with buffered solution and sham-operated group. Animals were killed 14 days after surgery, and lipid phosphorylation assays and immunoblotting were performed on the kidney homogenates. Results. More DAG was available in the UUO rats (2.4 ± 0.4 and 2.4 ± 0.3 vs 1.0 ± 0.2 pmol 32PA mg−1 min−1, in UUO and UUO + BMMC vs SHAM). Sphingosine kinase was 150 ± 12% more active in UUO + BMMC than in UUO and SHAM. Cer levels were 76 ± 7% lower in the UUO + BMMC than UUO. LPA receptor type 1 (LPA1) expression was 169 ± 7% higher in the UUO group than in UUO + BMMC and SHAM. BMMC maintain control levels of Ca2+-ATPase expression altered by UUO by 40%. Conclusions. BMMC infusion modulated diverse lipid signalling pathways and protein expression, shifted sphingolipid metabolism toward a regenerative pattern and favourably reduced the levels of a receptor involved in the progression of tissue fibrosis. These results strengthen the benefits of BMMC treatment and give insight into its paracrine mechanisms of action.