The lymphatic system is an important auxiliary system of tissue fluid reflux, which plays an important role in maintaining the dynamic balance of tissue fluid, lipid absorption, immune monitoring and other physiological processes. In many pathological conditions (such as inflammatory reactions, tissue wound repair, organ transplantation, and tumors), lymphatic vessel formation can be reactivated9,10. At present, research on lymphangiogenesis both domestically and internationally is mainly concentrated in the field of cancer, and the mechanism of lymphangiogenesis in DN is not clear. It is well known that inflammation is considered to be an important factor in lymphangiogenesis, and the involvement of inflammatory factors (such as interleukin-1 and tumor necrosis factor alpha) and macrophages can increase the production of vascular endothelial factors, thus promoting lymphangiogenesis11,12. In recent reports on human kidney diseases, we found that lymphangiogenesis is affected by the duration of inflammation and fibrosis progression, rather than acute inflammation. As a type of chronic interstitial inflammation, DN is characterized by mesangial dilatation, podocyte loss, glomerular proliferation, glomerular basement membrane thickening and tubular epithelial cell dysfunction, which leads to glomerular capillary occlusion; therefore, lymphatic vessel formation is considered a kind of renal edema and hypertension compensation response4,13,14.
DN is a serious complication of DM and initially manifests as microalbuminuria. Persistent diabetes-related metabolic and hemodynamic disorders can lead to inflammatory changes in the kidney, and promote the process from injury to repair of the kidney, leading to renal fibrosis, especially after stages III and IV, and the degree of renal fibrosis is more significant15,16. Many studies have shown that renal fibrosis is accompanied by lymphangiogenesis. One study induced renal fibrosis by constructing a unilateral ureteral obstruction model in mice and found that the degree of renal lymphangiogenesis was positively correlated with renal fibrosis17. To understand the relationship between lymphangiogenesis and renal fibrosis, another study used unilateral ureteral obstruction in rats to analyze the relationship between inflammation, fibrosis, lymphangiogenesis and growth factor expression; it was found that transforming growth factor-β 1 (TGF-β1) and VEGF-C were present in renal tubular epithelial cells and monocytes, where their levels gradually increased and reached a peak at 14 days after ureteral obstruction18. Sakamoto I et al, through pathological examination of 124 renal biopsy specimens, found an increase in lymphatic vessel number in patients with tubulointerstitial disease compared with the control group and that this was related to the degree of tissue damage; moreover, the correlation with the fibrotic area was stronger than that with the inflamed area. In addition, compared with other renal diseases, lymphangiogenesis in DN patients was more significant19. Therefore, lymphangiogenesis is a common feature of tubulointerstitial fibrosis.
The advantages and disadvantages of lymphangiogenesis in DN are still controversial. Lymphatic vessels, an important regulator of fluid balance, immune cell transport and immune recognition, play an important role in many diseases. DN is the main cause of end-stage renal disease worldwide. Hyperglycemia-induced oxidative stress and inflammation play an important role in the occurrence and development of DN. Lymphangiogenesis is an important part of the inflammatory process of tissues and organs. Many studies have shown that the dilated lymphatic system is necessary to resolve inflammation, and lymphatic vessels play an important role in fluid clearance and immune cell transport, thus achieving the effect of reducing or alleviating inflammation20,21. However, recent studies have shown that lymphangiogenesis is not necessarily beneficial to the progression of DN. Functional lymphatics play an important role in the process of body fluid balance and immune monitoring, but disordered expansion of lymphatics can lead to the failure of immune cell clearance, which leads to chronic inflammation. Recent studies have found that in DN mice, selective inhibition of VEGFR-3 to inhibit lymphatic proliferation could reduce the serum cholesterol level, free fatty acids and proteinuria, thus decreasing inflammation and oxidative stress in the kidney and alleviating renal fibrosis22. Another study also questioned the involvement of lymphatic function DN. With the development of chronic inflammation in DN, the expression of various inflammatory factors was not balanced, resulting in the excessive growth of lymphatic vessels, which eventually led to structural incompleteness and dysfunction. Studies have shown that by reducing renal lipid toxicity, renal lymphatic dysfunction can be alleviated in DN, thereby alleviating the degree of renal inflammation and fibrosis23.