Lack of the Growth Factor Midkine Enhances Survival against Cisplatin-Induced Renal Damage

Abstract

Although cisplatin acts directly on proximal tubule epithelial cells and causes cell death, little is known regarding the biological significance of its secondary effects, such as inflammation. The growth factor midkine is highly expressed in the proximal tubule and exerts ambivalent activities as to cisplatin nephrotoxicity, ie, anti-apoptotic and chemotactic ones. Here we report that midkine-deficient mice show a significantly higher survival rate than wild-type mice. The levels of blood urea nitrogen and tubular degeneration and apoptosis were higher in wild-type mice despite the anti-apoptotic activity of midkine. We found that recruitment of neutrophils was more enhanced in wild-type mice, this being consistent with the chemotactic activity of midkine. Midkine expression in wild-type mice persisted for 24 hours, and then dramatically decreased. Preadministration of midkine anti-sense oligodeoxyribonucleotide to wildtype mice suppressed midkine expression, and consequently neutrophil infiltration. It is of note that neutrophil infiltration, apoptosis, and elevation of blood urea nitrogen became conspicuous sequentially, namely 1, 2, and 3 days after cisplatin administration, respectively. These findings suggest that early molecular events involving midkine induce inflammatory response and their circuits eventually enhance the death of the proximal tubule epithelial cells. The results indicate the crucial role of inflammation in cisplatin-induced renal damage, and provide a candidate molecular target for its prevention. Cisplatin [cis-dichlorodiammine-platinum (II), CDDP] is widely used to treat carcinoma patients. However, its full clinical utility is significantly limited because of its nephrotoxicity. The main site of CDDP action is in proximal tubule epithelial cells. In proliferating cancer cells, CDDP inhibits DNA and RNA synthesis. In contrast, the effects of CDDP on nonproliferating cells, such as proximal tubule epithelial cells, can be categorized into mainly two primary types.

Clinical relevance of circulating midkine in ulcerative colitis

“…It may play a role in recruitment of neutrophils and macrophages into inflamed tissue (23,24), and up-regulation of synthesis of inflammatory mediators (25)(26)(27). Animal studies have revealed that several inflammation-related phenomena were substantially alleviated in midkine-deficient animals (12,25,(28)(29)(30)(31)(32). The mechanisms mentioned above may also operate in the involvement of midkine in the pathogenesis of UC since the accumulation of neutrophiles and monocytes associated with aberrant inflammatory response is essential for development of UC (14).…”

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

“…14 Second, Mdk À/À mice exhibit significantly milder phenotypes than Mdk þ / þ mice in models of arterial restenosis, ischemic reperfusioninduced renal damage, cisplatin-induced nephropathy and rheumatoid arthritis. [14][15][16][17] Finally, an MK antisense ODN ameliorates arterial restenosis, ischemic reperfusion-induced renal damage and cisplatin-induced nephropathy. [17][18][19] In addition to these indirect data on the relationship between MK and inflammation-related diseases, MK directly induces macrophage migration.…”

“…[14][15][16][17] Finally, an MK antisense ODN ameliorates arterial restenosis, ischemic reperfusion-induced renal damage and cisplatin-induced nephropathy. [17][18][19] In addition to these indirect data on the relationship between MK and inflammation-related diseases, MK directly induces macrophage migration. 15 We hypothesized that MK plays roles not only in mesangial pathological changes, but also in the inflammation associated with diabetic nephropathy.…”

Neuroglycan C Is a Novel Midkine Receptor Involved in Process Elongation of Oligodendroglial Precursor-like Cells

“…MK promotes neurite outgrowth and migration in neuronal cells isolated from the embryonic brain (5-7) and prevents apoptosis (8,9). MK also promotes the migration of inflammatory leukocytes (10) and thereby plays a key role in the etiology of neointima formation (10), renal injury (11,12), rheumatoid arthritis (13), and intraperitoneal adhesion after surgery (14). So far, protein-tyrosine phosphatase (7,15), anaplastic lymphoma kinase (16), low density-lipoprotein receptor-related protein-1 (17), low density lipoprotein receptor-related protein 6 (9), and integrin ␣4␤1 and ␣6␤1 (18) have been identified as MK receptors.…”