CN109674827B - Application of lactobacillus casei Zhang in improving acute kidney injury and preventing and treating renal interstitial fibrosis - Google Patents
Application of lactobacillus casei Zhang in improving acute kidney injury and preventing and treating renal interstitial fibrosis Download PDFInfo
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Abstract
The invention discloses a new application of lactobacillus casei Zhang (L.casei Zhang) in improving acute kidney injury and preventing and treating renal interstitial fibrosis. Through constructing a mouse bilateral kidney ischemia reperfusion kidney injury model, the result shows that: L.Casei Zhang can obviously improve renal function, alleviate TECs injury, reduce the secretion of inflammatory factors of the kidney and macrophage infiltration, reduce intestinal injury and inflammatory reaction, effectively improve intestinal permeability, simultaneously increase the weight of the kidney, reduce collagen deposition in the later stage of I/R and reduce the expression of fibrosis related factors alpha-SMA and Col-I, which shows that acute renal injury induced by I/R and secondary chronic renal interstitial fibrosis can be alleviated, and a basis is provided for clinical treatment of renal injury.
Description
Technical Field
The invention belongs to the medicineThe field of medicine, relates to lactobacillus caseiZhang (L.casei Zhang) Especially in improving acute kidney injury and preventing and treating renal interstitial fibrosis.
Background
In recent years, more and more researches prove that intestinal dysbacteriosis exists in Chronic Kidney Disease (CKD) patients, and the administration of probiotics can improve the intestinal dysbacteriosis and reduce the generation of uremic toxins, so that the CKD patients are benefited.
Since many probiotics are strain specific for the regulation of physiological function, it is crucial to select appropriate species for intervention based on their functional properties.L．Casei ZhangIs the first lactobacillus casei for completing independent research and development of metagenome sequencing in China. The Zhang peace group of professors has been confirmed by a number of studiesL．Casei ZhangThe bacillus subtilis has the effects of resisting inflammation, regulating lipid, improving insulin resistance, antagonizing enteropathogenic bacteria, reducing enterotoxin, preventing type 2 diabetes mellitus and colon cancer and the like, is clinically applied at present, but has no relevant report on the bacillus subtilis in preventing and treating kidney diseases.
Disclosure of Invention
The invention aims to provide lactobacillus caseiZhang (L.casei Zhang) The new application in improving acute kidney injury and preventing and treating renal interstitial fibrosis aims at providing a safe and effective prevention and treatment measure and better meeting the requirement of clinical medication of chronic kidney diseases.
The technical scheme for solving the technical problems is as follows:
lactobacillus casei is observed by constructing a mouse bilateral renal ischemia reperfusion (I/R) renal injury modelZhangThe effects on renal function, TECs injury, macrophage infiltration, inflammatory factor expression, intestinal barrier injury and renal weight/body weight ratio and chronic renal interstitial collagen fiber deposition of a model mouse are found as follows:L．Casei Zhangcan obviously improve renal function, relieve TECs injury, reduce the secretion of inflammatory factors of the kidney and macrophage infiltration, reduce intestinal injury and inflammatory reaction and effectively improve intestinal permeability.
The observation period is prolonged to 28 days, and the result shows that the kidney weight/body weight of the treatment group is obviously higher than that of the model group, and the treatment group can also obviously reduce collagen deposition in the I/R late stage and reduce the expression of fibrosis related factors alpha-SMA and Col-I.
The above results proveL．Casei ZhangCan obviously relieve I/R induced acute kidney injury and secondary chronic renal interstitial fibrosis, and provides basis for clinical application of treating kidney injury.
Drawings
FIG. 1 shows the colon tissue damage observed by HE staining and Occludin fluorescent staining of colon tissue.
Detailed Description
The present invention will be described in detail with reference to specific examples. It should be noted that the described embodiments are only used for explaining the invention, and are not used for limiting the invention. In addition, the experimental procedures described in the examples are all conventional techniques in the art, and those skilled in the art can refer to various common tool books, scientific documents, related specifications, manuals, and the like before the filing date of the present application.
Example 1
1. Material
In the experiment, SPF-grade 6-7 week male C57BL/6 mice (the weight is about 18-20g) purchased from Beijing Huafukang Biotechnology GmbH are bred in an SPF-grade barrier environment of an animal room of the college of medicine of Tongji of Huazhong university of science and technology, and the sterile feed and drinking water of the mice are provided by the animal room. After l weeks of acclimatization, the experimental animals were randomized into 5 groups of 10 animals each, each group being treated as follows:
dummy surgery group (Sham group): irrigating the stomach with normal saline;
model group (I/R group): molding after the stomach is irrigated with normal saline;
(iii) Lactobacillus casei general group (I/R + Lact group): filling common lactobacillus casei for 4 weeks before molding, and after molding, continuing filling until the common lactobacillus casei is killed;
(iv) Lactobacillus caseiL．Casei Zhang Group (I/R + Lac. z group): administered 4 weeks in advanceL．Casei
Zhang(1 x 109 CFU/d) after drenching, make the model, continue drenching until sacrifice.
The procedures for mouse feeding and operation were performed strictly according to the animal care committee of the institute of NIH, usa and the college of peer medical college of science and technology university in china. The normal saline is clinical medical normal saline, and ordinary lactobacillus is purchased from Taiwan Suzhou Biotech limited, Lactobacillus caseiL．Casei ZhangIs provided by Zhang and average professor in key laboratory of department of science and technology, university of inner Mongolia agriculture and university of dairy biotechnology and engineering education.
2. Method of producing a composite material
2.1 mouse bilateral renal ischemia-reperfusion (I/R) model construction
1) After weighing the mice, anesthetizing the mice by using 1% sodium pentobarbital at the concentration of 10 mu l/g, shaving off the hair on the backs of the mice, making the mice lie on a heating plate of a temperature controller, fixing the limbs by using an adhesive tape, inserting a probe of the temperature controller into the anus of the mice to monitor the anal temperature, and starting the operation when the body temperature is basically stabilized between 36.8 and 37.2 ℃.
2) Disinfecting the dorsal skin of a mouse by iodophor, longitudinally cutting the dorsal skin of the left side and the right side, exposing the kidney on the right side layer by layer, picking out the kidney by a draw hook made of a glass minute needle (the action needs to be gentle, the liver does not need to be injured by attention), fully exposing the pedicle of the right kidney, clamping the artery of the right kidney by a noninvasive arteriole clamp, and starting timing for 30 min.
3) The left kidney was exposed rapidly, the left kidney was also picked out with a glass retractor, the left renal pedicle was fully exposed, the left renal artery was clamped with a non-invasive arteriole clamp, and timing was started for 30 min. Preferably, the bilateral kidney clamp is not more than 1min apart.
4) The successful ischemia was confirmed by observing the bilateral kidney change from pink to purplish black, with the kidneys placed back into the abdominal cavity.
5) After 30min of clamping, the arteriolar clamp is gently taken down, the kidney is quickly restored to pink from purple black to prove that the reperfusion is successful, the kidney is reset, and about 300-.
6) The muscle and skin incisions of the mice are sutured layer by layer, and the body temperature of the mice needs to be controlled between 36.6 and 37.4 ℃ in the whole operation process.
7) The sutured mouse is wrapped with gauze, rewarmed with a constant temperature electric blanket, returned to the cage after it is ready to move, and the cage is marked.
Note: sham group (Sham group: only kidney exposed, but not renal artery occluded, other mice in the same ischemia reperfusion surgery group).
2.2 Collection of stool, Kidney, serum and Colon specimens
1) After operation, at 5d and 28d, the animal room is removed to collect the fecal tissue of the mouse, the back skin and tail of the mouse are held by hands, the mouse is stimulated to defecate, the fresh and clean fecal tissue of the mouse is collected in a sterile and enzyme-free 2.0ml EP tube (about 6-8 pieces are collected), the tube is sealed by sealing glue and then placed in an ice box, and the tube is stored in a refrigerator at-80 ℃ within 2h without repeated freezing and thawing.
2) Taking the mouse back to a laboratory, recording the weight of the mouse, pinching the dorsal skin and tail of the mouse, cutting off beards on two sides, picking up the eyeball of the mouse by using a bent forceps, collecting blood in a heparin anticoagulation tube, pressing the heart of the mouse while taking the blood, covering a cover of the anticoagulation tube after the blood is taken, quickly turning upside down to ensure that the blood is fully contacted with the anticoagulant, standing at room temperature for 30min, 3000rpm, centrifuging for 10min, subpackaging serum into a clean EP tube, sealing, storing at-80 ℃ for a long time, avoiding repeated freeze thawing, and quickly freezing the serum specimen for detecting metabonomics in liquid nitrogen and then storing at-80 ℃.
3) Taking blood, dislocating cervical vertebrae of a mouse, killing the mouse, fixing the mouse on a foam plate in a supine position, placing the foam plate in an enamel tray, quickly cutting off the pleuroperitoneal cavity of the mouse, inserting a perfusion needle into the most obvious heart tip beating position, exposing and cutting off inferior vena cava, perfusing with an ice PBS buffer solution (about 20 ml/mouse) at a constant speed slowly, and finishing perfusion when clear liquid flows out of the inferior vena cava.
4) Kidney, spleen, and colon tissues were sequentially harvested, placed in ice PBS, fascia was stripped from kidney and spleen, excess water was blotted with filter paper, weighed, and recorded.
5) The kidney specimen was cut into two halves with a knife blade coronal plane, one half was fixed in 4% paraformaldehyde tissue fixative for 24h, 1/3 of the other half kidney was left for PCR, 2/3 was left for Western blot, the tissue was placed in a clean EP tube and stored in a refrigerator at-80 ℃ for a long period of time. The kidney tissue specimen for detecting metabonomics needs to be rapidly frozen in liquid nitrogen and then stored at-80 ℃.
6) The stool in the colon tissue is washed clean by ice PBS, then the tissue is placed in ice PBS to be shaken and washed for 3 times, each time for 3min, and the colon tissue at the small fixed part is cut and fixed in 4 percent paraformaldehyde.
7) After kidney tissues and colon tissues are fixed for 24 hours, the kidney tissues and the colon tissues are put into a dehydrator to be dehydrated and waxed, after dehydration is completed, the same group of mouse tissues are embedded into a wax block, the kidney tissues and the colon tissues are separately embedded, and marking is done.
8) Slicing: cutting the wax block into slices of 3-4 μm with a paraffin slicer, spreading on a glass slide, drying, marking, placing in a slice box, and storing at normal temperature.
2.3 detection index and method
Detecting the serum creatinine and urea nitrogen level of the mouse by using a blood biochemical kit; periodic acid-colorless fuchsin (PAS) staining to observe kidney tissue damage; LTL staining to detect the brush border condition of the proximal tubule of each group of kidney; performing immunofluorescence detection on the expression of Kim-1 and F4/80; detecting the expression change of inflammatory factors (IL-1 beta, IL-6, TNF-alpha and IL-10) in kidney tissues by real-time fluorescent quantitative PCR (RT-PCR); observing the damage condition of colon tissues by HE staining and Occludin fluorescent staining of the colon tissues; masson staining is used for observing the fibrosis condition of the kidney tissues; performing immunofluorescence detection on the expression of the alpha-SMA and the Collagen-I; western blot detection of kidney tissue alpha-SMA protein expression.
3. Results and analysis
1）L．Casei ZhangEffects on serum creatinine and urea nitrogen in mice. After 5d of moldingThe results of the mouse serum creatinine and urea nitrogen detection are shown in table 1, and it can be seen that,L．Casei Zhangintervention can reduce serum urea and creatinine in a renal ischemia reperfusion mouse model, indicating that renal function of I/R-induced acute renal injury can be improved.
TABLE 1 mouse serum creatinine and Urea Nitrogen levels after model 5d
P <0.05 compared to I/R group.
2）L．Casei ZhangEffects on injury to TECs. According to PAS pathological staining, the mice in the I/R group have the symptoms of necrosis of renal tubules, tubular formation, tubular expansion, edema, brush border loss and the like, which indicate that the mice are seriously injured, the I/R + Lact group and the I/R + Lac.z group can reduce the renal tubule injury to different degrees, and the score of the renal tubule injury is shown in a table 2; from the LTL immunofluorescent staining, it was observed that the number of proximal tubule brush borders of kidney was decreased in the I/R group mice, while the number of proximal tubule brush borders of kidney was increased to different degrees in the I/R + Lact and I/R + Lac.z groups, and the results are shown in Table 3; an increase in Kim-1 expression was also observed in the I/R group, while the Kim-1 expression decreased to different degrees in both the I/R + Lact and I/R + Lac.z groups, as shown in Table 4. The above results show thatL．Casei ZhangCan obviously relieve the injury of the TECs caused by renal ischemia-reperfusion.
Table 2 effect of different treatment groups on renal tubular injury score
P <0.05 compared to I/R group.
TABLE 3 Effect of different treatment groups on the number of brush borders of the proximal tubule of the kidney
P <0.05 compared to I/R group.
TABLE 4 influence of different treatment groups on Kim-1 expression levels
P <0.05 compared to I/R group.
3）L．Casei ZhangThe effect on macrophage infiltration. F4/80 immunofluorescence staining detects macrophages, a large amount of macrophage infiltration appears in renal interstitium of mice in an I/R group, the infiltration of the renal interstitium macrophages can be reduced to different degrees in an I/R + Lact group and an I/R + Lac.z group, andL．Casei Zhangthe effect is obviously better than that of the common lactobacillus casei, the result is shown in a table 5, and the description shows thatL．Casei ZhangCan obviously reduce macrophage infiltration caused by renal ischemia reperfusion.
TABLE 5 macrophage infiltration in different treatment groups
P <0.05 compared to I/R group.
4）L．Casei Zhang Effects on the expression of inflammatory factors. Real-time fluorescence quantitative PCR (RT-PCR) is used for detecting the expression change of inflammatory factors (IL-1 beta, IL-6, TNF-alpha and IL-10) in kidney tissues, and the results show that the I/R + Lact group and the I/R + Lac.z group can reduce the secretion of proinflammatory factors IL-1 beta, IL-6 and TNF-alpha of kidney to different degrees and increase the secretion of the inflammation-inhibiting factor IL-10, the results are shown in Table 6, and the results show thatL．Casei ZhangCan obviously reduce inflammatory factors after renal ischemia reperfusion injury.
TABLE 6 Effect of different treatment groups on inflammatory factor expression
P <0.05 compared to I/R group.
5）L．Casei ZhangThe effects on intestinal barrier damage. The I/R can cause intestinal inflammation and injury, mainly manifested by inflammatory reaction and intestinal tight junction protein deletion, colon tissue HE staining shows that probiotic intervention can obviously relieve intestinal inflammation injury, and fluorescence staining of intestinal tight junction protein Occludin shows that probiotic groups are all obviously increased, and the result is shown in figure 1, which illustrates thatL．Casei Zhang Obviously improve the intestinal permeability after the renal ischemia reperfusion injury.
6）L．Casei ZhangEffect on kidney/body weight ratio in mice. After I/R modeling for 28 days, the kidney tissues can be obviously atrophied, the kidney atrophy is obviously improved in a probiotic intervention group compared with an I/R group, the weight ratio of the kidney is obviously increased, and the results are shown in Table 7, which indicates thatL．Casei ZhangCan improve renal atrophy induced by renal ischemia reperfusion injury.
TABLE 7 Kidney/body weight ratio of mice in different treatment groups
P <0.05 compared to I/R group.
7）L．Casei Zhang Effects on chronic renal interstitial collagen fiber deposition. After I/R modeling for 28d, Masson pathological staining shows that the deposition of the renal interstitial collagen fibers of the probiotic group is obviously reduced,L．Casei Zhangthe group has obvious effect compared with the common lactobacillus acidophilus group, and the result is shown in table 8; meanwhile, the immunofluorescence detection also observes that the expression levels of the alpha-SMA and the Collagen-I in the I/R group are increased, while the expression levels of the alpha-SMA and the Collagen-I in the I/R + Lact group and the I/R + Lac.z group are reduced to different degrees, and the results are shown in Table 9; western Blot assay also confirmed a significant reduction in α -SMA expression in kidney tissue of probiotic groups, with results shown in Table 10. The above results show thatL．Casei Zhang Can obviously relieve the chronic renal interstitial collagen fiber deposition induced by the renal ischemia-reperfusion injury.
TABLE 8 Masson pathological staining of different treatment groups
P <0.05 compared to I/R group.
TABLE 9 influence of different treatment groups on the expression levels of alpha-SMA and Collagen-I
P <0.05 compared to I/R group.
TABLE 10 WB examination of the expression level of alpha-SMA in different treatment groups
P <0.05 compared to I/R group.
And (4) conclusion: through PAS pathological staining and LTL and KIM-1 immunofluorescence stainingL．Casei ZhangCan obviously reduce the damage of the TECs; RT-PCR result suggestionL．Casei ZhangDecreased secretion of inflammatory factors of the kidney after treatment; immunofluorescence detectionL．Casei ZhangMacrophage infiltration was significantly reduced in the treated group; colon HE staining showsL．Casei ZhangThe treatment effectively reduces intestinal injury and inflammatory reaction after kidney I/R; results of Occludin fluorescent staining confirmedL．Casei Zhang Can effectively improve intestinal permeability after kidney I/R.
Extend the observation period to 28 daysL．Casei ZhangLong term effects on renal injury, resulting in the discovery of the treatment group (Lactobacillus casei general group andL．Casei Zhanggroup) was significantly higher in kidney weight/body weight than the I/R group, and the treatment group (especially, the treatment group was found using Masson's pathological stainingL．Casei ZhangGroup) obviously reduces collagen deposition in the later stage of I/R, and immunofluorescence results show that fibrosis related factors alpha-SMA and Col-I are in the probiotic intervention groupAre all significantly reduced. WB also showed a significant reduction in α -SMA in the probiotic intervention group.
The above results show that, compared to Lactobacillus casei,L．Casei Zhangcan obviously relieve I/R induced acute kidney injury and secondary chronic renal interstitial fibrosis, and provides basis for clinical treatment of kidney injury.
Claims (1)
1. Lactobacillus caseiZhang（Lactobacillus casei Zhang) The application in preparing the medicine for treating acute kidney injury and secondary chronic renal interstitial fibrosis.
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| "Lactobacillus casei beneficially modulates immuno-coagulative response in an endotoxemia model";Haro Cecilia, et al.;《Blood Coagulation & Fibrinolysis》;20180131;摘要 * |
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