The role of Midkine in chronic kidney disease and vascular disorders

Abstract

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality in Australia and worldwide. Leukocytes, cytokine factors and extracellular matrix are major components of inflammation and fibrosis that activate irreversible, self-perpetuating damage responses in the kidney during CKD progression towards renal failure, which include glomerulosclerosis and tubulointerstitial injury. Understanding the critical factors that mediate renal pro-inflammatory and fibrotic responses will aid in the identification of diagnostic markers, and development of therapeutic strategies for CKD, which are currently limited. Cardiovascular disease (CVD) is a major determinant of worsening outcomes for CKD patients. Vascular calcification (VC) is an aberrant vascular pathology that predisposes CKD patients to increased cardiovascular risk, and is mediated by processes including hormonal dysregulations, bone-mineral disorders, atherosclerosis, and inflammation. Currently, robust prognostic markers or treatment strategies against VC have not been identified. Midkine (MK) is a growth factor that displays a range of biological functions. The mitogenic properties of MK are primarily recognised in development and cancer, whereas its angiogenic, immunomodulatory, and bone-related functions are implicated in kidney, cardiovascular and bone diseases. Studies to date have suggested that MK plays a pathological role in mediating the pathogenesis and progression of acute and chronic renal injury, cardiac dysfunction, atherosclerosis, and bone-mineral disorders by regulating pro-inflammatory, angiogenic and osteogenic responses. However, the role of MK in these processes, as well as its therapeutic potential in kidney, cardiovascular and bone diseases has yet to be clarified. The first aim of these studies was to determine the role of MK in correspondence with renal inflammation, fibrosis and injury outcomes in experimental models, as well as human renal biopsies of CKD and acute kidney injury (AKI). Additionally, the therapeutic efficacy of blocking MK action in an experimental kidney disease model was also investigated. Using the Adriamycin nephropathy (AN) model in mouse, increased MK expression and accumulation was found in the kidney glomeruli, tubules and tubulointerstitium of mice with AN in contrast to that of normal mice, and positively correlated with the degree of glomerular and tubulointerstitial injury. Increased MK expression and accumulation was also positively correlated with infiltration of macrophages and T lymphocytes, and expression of chemokines in normal and AN-induced mice. These results were similarly reflected in endothelial nitric oxide synthase knockout mice with Streptozotocin-induced diabetic nephropathy, mice with serum-induced anti-glomerular basement disease, and mice with ischaemia-reperfusion injury-induced AKI, where MK accumulation was quantitatively increased in glomerular, tubular and tubulointerstitial compartments of the kidney. Consistent with these findings, quantitatively increased MK accumulation was mostly found in the glomerular and tubulointerstitial compartments in renal biopsies of patients with various acute and chronic kidney diseases, such as lupus nephritis, diabetic nephropathy, focal segmental glomerulosclerosis and interstitial nephritis. Furthermore, increased MK accumulation was also associated with worse tubular atrophy and interstitial fibrosis, as well as infiltration of macrophages and T lymphocytes in human renal biopsies. Collectively, these results indicate that MK expressed or accumulated in the kidney is associated with pro-inflammatory and fibrotic responses that correspond with worsening renal injury outcomes in both mouse and human kidney diseases. Prophylactic administration of neutralising antibodies against circulating MK did not protect against renal injury outcomes in the AN model, suggesting that blocking the action of circulating MK is not a useful therapeutic option to consider for CKD. The second aim of these studies was to investigate the role of MK, and the therapeutic efficacy of blocking its action in VC. Using the vitamin D-induced VC model in mice, the preliminary results showed that prophylactic administration of neutralising antibodies against circulating MK quantitatively reduced the degree of aortic calcification in vitamin D-induced mice in contrast to those without antibody treatment. These results suggest that MK may be a pathological factor involved in mediating VC, and that blocking MK action may be a potential therapeutic option. The third aim of these studies was to determine whether serum MK could be a useful biomarker for longitudinal renal function decline, subclinical measures of VC and atherosclerosis, and clinical outcomes of CKD and CVD. In prospective cohort studies of generally healthy, elderly women, serum levels of MK were not associated with long-term renal function decline, and CKD-related hospitalisations and deaths. However, high levels of serum MK were associated with long-term development of subclinical measures of VC and atherosclerosis, such as abdominal aortic calcification and increased carotid artery intimal medial thickness, as well CVD-related clinical events, namely heart failure-related hospitalisations and deaths, independent of major risk factors such as age, smoking and renal function. These results suggest that serum MK could be a useful clinical biomarker for CVD, but not CKD-associated outcomes. Collectively, these findings demonstrate that MK may be a pathological factor involved in mediating progressive renal inflammation and injury, and VC in experimental kidney disease and VC models, respectively. Additionally, MK could be a promising biomarker for clinical CVD. Further studies into the specific mechanism(s) of action, and clinical relevance of MK with renal injury and VC will provide a better understanding of its therapeutic potential for the treatment of CKD and CVD.