Unfractionated bone marrow cells attenuate paraquat-induced glomerular injury and acute renal failure by modulating the inflammatory response

Paraquat (1,1′-dimethyl-4,4′-bipyridylium dichloride; PQ) is a non-selective herbicide, defoliant, and desiccant that has been widely and commonly used worldwide since the 1960 s1,2. Most cases of PQ intoxication result from suicide attempts or accidental exposure3. Following ingestion, PQ is rapidly distributed to various tissues, especially the kidney, lung and liver4. At 3 hours after PQ exposure, the concentration is highest in the kidney and leads to acute kidney injury (AKI), which magnifies the toxicity in the lung and other organs5,6. In PQ-induced AKI, patients usually develop tubular degeneration and formation of granular eosinophilic cytoplasm in the proximal and distal convoluted tubules5. In clinical practice, immunosuppressive therapy including methylprednisolone (MP), cyclophosphamide (CP), and dexamethasone (DEX) has been prescribed for the treatment of PQ poisoning, although the mortality rate remains high7,8. PQ is not removed by dialysis, and hemodialysis is used only as a supportive treatment for patients who develop kidney failure9. Thus, maintaining renal function in patients suffering from PQ poisoning remains a therapeutically important treatment strategy10,11. However, there is no specific antidote or effective therapy for PQ poisoning; therefore, effective therapies are urgently needed. The mechanism of PQ toxicity involves a series of cyclic reduction-oxidation reactions, with sequential depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and generation of PQ radicals and reactive oxygen species (ROS)12,13. The following pathological changes can be observed after PQ exposure: (1) the renal tubules lose their characteristic appearance, and their lining epithelial cells develop cytoplasmic vacuolation; (2) the glomerulus becomes degenerated, and the renal blood vessels become congested; and (3) the inter-tubular spaces are infiltrated by inflammatory leukocytes14. However, the specific mechanisms of PQ-induced AKI have not been fully elucidated. The concept of bone marrow-derived cells engraftment involves the differentiation of these cells into functional somatic cells capable of repairing injured tissue. Additionally, bone marrow-derived cells transplantation may support the healing of damaged tissues by exerting potent immunosuppressive effects and secreting soluble factors that regulate the pro-inflammatory cascade to promote tissue remodeling and cellular regeneration15. Many studies have shown that bone marrow-derived cells may be involved in tissue turnover and regeneration, including in the kidney. In particular, unfractionated bone marrow cells (BMCs) have been shown to regenerate tissue after cisplatin-induced acute tubular injury, improve renal function and ameliorate inflammation16. The selective recruitment and localization of bone marrow-derived cells to the kidney vasculature result in structural and functional recovery, as well as increased survival17. Bone marrow cells are incorporated into the glomerulus during recovery from experimentally induced glomerulonephritis18, and bone marrow-derived cells transplantation led to the formation of bone marrow-derived podocytes and mesangial cells in a mouse model of Alport’s syndrome, a hereditary nephropathy19. Given the poor prognosis of AKI, the promise of bone marrow-derived cells transplantation therapy to aid regeneration and organ recovery is an attractive therapeutic strategy. Oxidative stress and renal tubule injury are important factors in AKI caused by PQ poisoning. Currently, anti-oxidative stress therapy and glucocorticoid treatments are clinically applied. However, the survival rates of patients with PQ poisoning still remain as low. Novel insights into the toxicity mechanisms and potential therapeutic strategy developments are promising to reduce the high mortality of PQ poisoning. In the present study, we first attempted to characterize the mechanisms of PQ-induced toxicity in C57BL/6 mice, including the survival rate, degree of renal function, and pathological alterations. Furthermore, we sought to evaluate whether BMCs were capable of minimizing or preventing kidney injuries induced by PQ. Inflammatory cytokine and chemokine analysis was performed to assess the potential of BMCs transplantation in reducing PQ-induced nephrotoxicity.