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. 2019 Jun 6;19(1):118.
doi: 10.1186/s12906-019-2531-7.

The effects of a hirudin/liposome complex on a diabetic nephropathy rat model

Hongwu Wang  1 , Huantian Cui  2 , Lan Lin  3 , Yue Ji  2 , Qing Ni  3 , Junchen Li  2 , Jianli Pang  4 , Gongyan Bing  5 , Yuhong Bian  2
Affiliations

The effects of a hirudin/liposome complex on a diabetic nephropathy rat model

Hongwu Wang et al. BMC Complement Altern Med. .

Abstract

Background: Hirudin, an extract from Hirudo spp., is an anticoagulant used to treat a variety of renal diseases, including diabetic nephropathy (DN). Currently, hirudin has to be used at high dosages to treat DN because it poorly targets the kidneys, although at high dosages it can have severe side effects. Developing a targeted drug delivery system for hirudin, then, could boost its positive therapeutic effects while lowering the risk of side effects. Liposomes have been demonstrated to have significant renal targeting potential, but here we show that a hirudin-loaded liposome is an effective delivery method for patients with DN.

Method: In this study, we prepared a hirudin/liposome complex and tested its efficacy by injecting it into a rat model. We then compared the renal accumulation of hirudin between complex-injected rat models and rat models that received injections of hirudin alone. We also investigated the mechanisms behind the complex's effects.

Result: The hirudin/liposome complex increased the accumulation of hirudin in kidney tissues and relieved the renal injury in DN rat models. Moreover, the hirudin/liposome complex down-regulated the expression of TGF-β1 and VEGF in the kidneys.

Conclusion: We demonstrated that a hirudin/liposome complex can have a significant positive effect on DN. The mechanism may be that the complex inhibits the expression of VEGF and TGF-β1.

Keywords: Diabetic nephropathy; Hirudin/liposome complex; Target therapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a TEM image of liposome; and b) the hirudin/liposome complex
Fig. 2
Fig. 2
DLS spectra showing the particle size of the liposome and the hirudin/liposome complex did not change significantly within one week
Fig. 3
Fig. 3
In vitro time-dependent hirudin release from hirudin/liposome complex at 4 °C and 37 °C respectively
Fig. 4
Fig. 4
Six hours after injection of the hirudin/liposome complex, hirudin levels in the kidneys were significantly higher in hirudin/liposome complex-treated rats compared with the hirudin-treated rats. Hirudin treated rats (n = 10); Hirudin/liposome complex treated rats (n = 10). **:P<0.01 compared with hirudin-treated rats
Fig. 5
Fig. 5
After STZ injection, levels of blood glucose in the Model, Liposome, Hirudin and the Hirudin/liposome complex groups were significantly higher compared with the Control group, although the hirudin/liposome complex treatment did not lead to a decrease in the blood glucose level in DN rat models. Control group (n = 10), model group (n = 7), liposome group (n = 7), hirudin group (n = 8), hirudin/liposome complex group (n = 7):P<0.05;*:P<0.01
Fig. 6
Fig. 6
The hirudin/liposome complex treatment reduced the levels of serum BUN (a), Cr (b), and 24-h urine protein (c) in DN rat models. Control group (n = 10), Model group (n = 7), Liposome group (n = 7), Hirudin group (n = 8), Hirudin/liposome complex group (n = 7). ##:P<0.01 compared with the Control group; *:P<0.05 compared with the Model group;**:P<0.01 compared with the Model group
Fig. 7
Fig. 7
HE staining indicated that pathological changes including the hyperplasia of the glomerular mesangial matrix, tubular atrophying and infiltration of inflammatory cells could be noted in Model group. The hirudin/liposome complex treatment reduced the atrophying of kidney tubules and infiltration of inflammatory cells in the DN rat model. (Red arrows indicate hyperplasia of the glomerular mesangial matrix; black arrows indicate atrophying of kidney tubules; blue arrows indicate infiltration of inflammatory cells, 20x). Control group (n = 10), Model group (n = 7), Liposome group (n = 7), Hirudin group (n = 8), Hirudin/liposome complex group (n = 7)
Fig. 8
Fig. 8
Gene expression of VEGF (a) and TGF-β1 (b) in the kidneys was down-regulated in the Hirudin/liposome complex group compared with the Model group. Control group (n = 10), Model group (n = 7), Liposome group (n = 7), Hirudin group (n = 8), Hirudin/liposome complex group (n = 7). ##:P<0.01 compared with Control group; *:P<0.05 compared with Model group
Fig. 9
Fig. 9
The negative controls of VEGF (a) and TGF-β1 (b) and pre-adsorbtion controls of VEGF (c) and TGF-β1 (d) showed a complete abolishment of specific signals for all antibodies. Positive contols for VEGF (e) and TGF-β1 (f) staining showed a apecific staining partterns in the vascular epithilial cells for VEGF and in the stroma cells for TGF-β1(40x)
Fig. 10
Fig. 10
Immustaining indicated that VEGF levels in the epithelium of the glomerulus (a, c) and TGF-β1 (b, d) levels in the stroma of the glomerulus and kidney tubules were decreased in the Hirudin/liposome complex group compared with the Model group (40x). Control group (n = 10), Model group (n = 7), Liposome group (n = 7), Hirudin group (n = 8), Hirudin/liposome complex group (n = 7). ##:P<0.01 compared with Control group; *:P<0.05 compared with Model group;**:P<0.01 compared with Model group
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