CN112933232A

CN112933232A - Application of PGC-1 alpha activated TFEB mediated autophagy in preparation of medicine for treating acute kidney injury

Info

Publication number: CN112933232A
Application number: CN202110140570.0A
Authority: CN
Inventors: 袁玉佳; 袁龙辉; 陆燕蓉; 程惊秋
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-02-02
Filing date: 2021-02-02
Publication date: 2021-06-11

Abstract

The invention relates to the field of biological medicines, in particular to application of PGC-1 alpha activated TFEB mediated autophagy in preparation of a medicine for treating acute kidney injury. The experimental result shows that the PGC-1 alpha small molecule agonist ZLN005 can promote autophagy of cells to remove damaged mitochondria and improve the functions of the mitochondria by activating TFEB, thereby reducing the AKI injury induced by Cisp.

Description

Application of PGC-1 alpha activated TFEB mediated autophagy in preparation of medicine for treating acute kidney injury

Technical Field

The invention relates to the field of biological medicines, in particular to application of PGC-1 alpha activated TFEB mediated autophagy in preparation of a medicine for treating acute kidney injury.

Background

Acute Kidney Injury (AKI) is a syndrome characterized primarily by a rapid decrease in renal excretion function, and injury and death of tubular cells are key pathological features of AKI. AKI is a common clinical critical disease, has high morbidity and mortality, and still has high mortality under the current treatment means. Cisplatin (cissplatin, Cisp) is one of the commonly used antitumor drugs for clinical chemotherapy, wherein nephrotoxicity is the main side effect of Cisp, and therefore, Cisplatin is commonly used for establishing an AKI (angiotensin converting enzyme) induction model and treating and researching AKI. Several studies have shown that Cisp induces tubular cell injury through a variety of signaling pathways and factors, and mitochondrial dysfunction plays an important role in pathogenesis in Cisp-induced AKI. ROS production, mitochondrial membrane potential drop, and mitochondrial function impairment, ultimately leading to kidney damage.

Autophagy is a dynamic self-degradation process in eukaryotic cells mediated by lysosomes that degrades damaged mitochondria, misfolded proteins, DNA, and other organelles. Autophagy is classified into selective autophagy and nonselective autophagy, and mitophagy is one of selective autophagy, identifies damaged mitochondria and degrades, maintaining quality control of mitochondria. Numerous studies have shown that basal autophagy in the kidney plays a crucial role in maintaining tubular homeostasis. Deletion or down-regulation of autophagy-critical genes exacerbates oxidative stress and mitochondrial damage, leading to renal dysfunction, whereas activation of autophagy in renal ischemia-reperfusion models can protect renal tubular cells by reducing mitochondrial damage and ROS production. It can be seen that autophagy plays an important role in improving renal dysfunction and mitochondrial damage in AKI.

Therefore, it is of great practical significance to provide a drug for alleviating acute kidney injury by activating autophagy.

Disclosure of Invention

In view of the above, the present invention provides an application of PGC-1 α activating TFEB mediated autophagy in the preparation of a medicament for treating acute kidney injury. The experimental result shows that the PGC-1 alpha small molecule agonist ZLN005 can promote autophagy of cells to remove damaged mitochondria and improve the functions of the mitochondria by activating TFEB, thereby reducing the AKI injury induced by Cisp.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides application of PGC-1 alpha overexpression in preparation of a medicine for treating and/or preventing kidney diseases.

In addition, the invention also provides application of the PGC-1 alpha transcription regulator in preparing a medicament for treating and/or preventing kidney diseases.

In some embodiments of the invention, the transcriptional modulator of PGC-1 α comprises ZLN005(2- (4-tert-butylphenyl) benzimidazole).

In some embodiments of the invention, the transcriptional modulator of PGC-1 α further activates TFEB-mediated clearance of damaged mitochondria by activating the transcriptional level of PGC-1 α.

In some embodiments of the invention, the transcriptional modulator of PGC-1 α is capable of ameliorating mitochondrial dysfunction in renal tubular epithelial cells.

In some embodiments of the invention, the kidney disease comprises Cisp-induced acute kidney injury.

On the basis of the research, the invention also provides a medicine for treating and/or preventing kidney diseases, which comprises a PGC-1 alpha transcription regulator and pharmaceutically acceptable auxiliary materials.

In conclusion, the experimental results show that the PGC-1 alpha small molecule agonist ZLN005 can promote autophagy of cells to remove damaged mitochondria by activating TFEB, improve mitochondrial function and further reduce the AKI damage induced by Cisp.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 shows the down-regulation of PGC-1 α expression in a mouse model of AKI. C57BL/6 single intraperitoneal injection of Cisp (16mg/kg, i.p.) induced AKI; (A) detecting serum creatinine urea nitrogen; (B) HE and PAS detection; (C) WB detecting the expression level of PGC-1 alpha;

FIG. 2 shows that PGC-1 α ameliorates Cisp-induced injury of HK2 cells. HK2 cells were treated with Cisp (2.5. mu.M, 5. mu.M, 10. mu.M) for 48 h; (A) CCK8 test for cell viability; (B) flow detection of Cisp induced apoptosis of HK2 cells; (C) WB detects the expression levels of apoptosis-related proteins (Bax and Bcl-2) and PGC-1 alpha; (D) and (E) detecting the level of apoptosis by overexpressing PGC-1 α;

FIG. 3 shows that in vitro, pharmacological activation of PGC-1 by ZLN005 inhibited Cisp-induced injury; ZLN005 (10. mu.M) intervened in Cisp (5. mu.M) treated HK2 cells; (A) CCK8 test for cell viability; (B) WB detects the expression levels of apoptosis-related proteins (Bax and Bcl-2) and PGC-1 alpha; (C) flow assay ZLN005 for its effect on Cisp-induced apoptosis;

FIG. 4 shows that oral gavage ZLN005 prevents Cisp-induced AKI; c57BL/6 single intraperitoneal Cisp (16mg/kg, i.p.) induction of AKI, ZLN005(15mg/kg/d, i.g.) intervention for 4 days; (A) detecting serum creatinine urea nitrogen; (B) HE and PAS detection; (C) performing immunohistochemical detection; (D) WB detects the expression levels of apoptosis-related proteins (Bax and Bcl-2) and PGC-1 alpha; (E) tunnel staining to detect apoptosis;

FIG. 5 shows ZLN005 activation of PGC-1 α inhibits Cisp-induced mitochondrial damage; (A) and (B) MitoSOX Red detects mitochondrial ROS; (C) JC-1 detecting mitochondrial membrane potential; (D) WB detects the expression of mitochondrial associated proteins (ATP5b and Ndufs 4); (E) detecting the ATP content by an ATP kit;

FIG. 6 shows that PGC-1 α activates autophagy by modulating TFEB; (A) the co-immunoprecipitation experiment proves that PGC-1 alpha and TFEB have interaction; (B) WB measures the expression levels of P62 and LC3 proteins in Cisp-treated HK2 cells in the presence or absence of HCQ; (C) in the presence or absence of ZLN005, the WB of Cisp-treated HK2 cells detected the expression levels of TFEB, P62 and lc3 proteins; (D) RT-PCR examined the expression level of P62 mRNA in ZLN 005-treated HK2 cells; (E) immunofluorescence detects the co-localization of mitochondria and autophagosomes;

FIG. 7 shows that silencing TFEB moiety abolished ZLN005 protection of Cisp-treated HK2 cells; HK2 cells were transfected with control siRNA and TFEB siRNA for 6h, and then treated with Cisp or ZLN005 for 48 h; (A) WB measures autophagy-related protein (TFEB, P62 and LC3) expression levels; (B) WB detects expression levels of mitochondrial associated proteins (ATP5b and Ndufs 4); (C) MitoSOX detects mitochondrial ROS levels; (D) WB detecting the expression level of apoptosis-related protein; (E) flow assay ZLN005 for its effect on Cisp-induced apoptosis; (F) detecting the ATP content by an ATP kit;

FIG. 8 shows ZLN005 reduced Cisp-induced kidney injury in AKI mice via the PGC-1a/TFEB pathway; (A) WB measures autophagy-related protein (TFEB, P62 and LC3) expression levels; (B) detecting the mitochondrial morphology of the renal tubular epithelial cells by an electron microscope; (C) WB detects expression levels of mitochondrial associated proteins (ATP5b and Ndufs 4); (D) MitoSOX Red detects fresh kidney cryo-section mitochondrial ROS levels.

Detailed Description

The invention discloses application of PGC-1 alpha activated TFEB mediated autophagy in preparation of a medicament for treating acute kidney injury, and a person skilled in the art can realize the application by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator 1) is a multifunctional coactivator, and can promote mitochondrial biosynthesis. The expression of PGC-1 alpha is obviously reduced in the development process of diabetic nephropathy and renal fibrosis, and the fact that PGC-1 alpha plays an important role in the kidney protection is suggested. In Cisp-induced AKI, deficiency of tubular PGC-1 α proximal to the kidney exacerbates tubular injury and renal dysfunction, however, different strategies to enhance PGC-1 α expression may be effective in alleviating diabetic nephropathy and renal fibrotic injury. In vascular smooth muscle cells, defects in PGC-1 α disrupt lysosomal function and autophagy flux, and more importantly, PGC-1 α reduces protein toxicity in Huntington's chorea by promoting activation of the important regulator of autophagosomal TFEB, suggesting that PGC-1 α may regulate autophagy levels via TFEB.

The small molecule compound ZLN005(2- (4-tert-butylphenyl) benzimidazole) is a transcription regulator of PGC-1 alpha, and plays an anti-diabetic role by transcriptionally activating PGC-1 alpha in skeletal muscle, and it has been reported that ZLN005 inhibits hyperglycemia-induced myocardial cell injury by promoting SIRT1 expression and activation of autophagy. ZLN005 has a potential protective role in coronary artery disease as well as neurodegenerative disease, however, the role of ZLN005 in Cisp-induced AKI has not been reported.

Therefore, the invention establishes a human tubular epithelial cell (HK2) damage model and a mouse AKI model by Cisp respectively, intervenes ZLN005, and observes whether ZLN005 can further activate TFEB (TFEB) mediated autophagy to remove damaged mitochondria by activating the transcription level of PGC-1 alpha, improves the mitochondrial dysfunction of the tubular epithelial cells, and relieves acute kidney injury induced by Cisp.

The PGC-1 alpha activates the application of TFEB mediated autophagy in preparing the medicine for treating acute kidney injury, and the used raw materials and reagents can be purchased from the market.

The invention is further illustrated by the following examples:

example 1 Effect of PGC-1 α in Cisp-induced HK2 cell injury

In vitro constructing a Cisp (5 mu M, 48h) induced HK2 cell model, detecting cell activity through CCK8, detecting apoptosis through Annexin V/PI flow and detecting expression level changes of apoptosis-related proteins Bax and Bcl2 through WB. Subsequently, PGC-1 alpha is activated by PGC-1 alpha plasmid overexpression or a small molecule agonist ZLN005, the cell activity is detected by CCK8, the apoptosis is detected by Annexin V/PI flow, and WB is detected to detect the expression level change of apoptosis-related proteins Bax and Bcl 2. And then detecting changes such as mitochondrial membrane potential and ATP content by a flow-type detection mitochondrial ROS and JC-1 dyeing detection mitochondrial membrane potential and an ATP kit.

The results of FIGS. 2-5 show that:

cisp (5 μ M, 48h) induced cell damage and mitochondrial dysfunction of HK2, mainly manifested by a marked decrease in cell activity, an increase in mitochondrial ROS levels, a decrease in mitochondrial membrane potential and a decrease in ATP content.

Cisp induces increased activity of HK2 cells, inhibited apoptosis, reduced mitochondrial ROS levels, increased mitochondrial membrane potential and increased ATP levels by over-expressing PGC-1 α plasmid or ZLN005(10 μ M).

TABLE 1

Figure2-A	Con	Cisp-2.5	Cisp-5	Cisp-10	Cisp-20
							1	0.82475	0.625637	0.377759	0.210102
	1.001174	0.836202	0.696088	0.425665	0.216588
							1.043003	0.792942	0.506431	0.452739	0.243297
Mean value	1.014725667	0.817964667	0.609385333	0.418721	0.223329
						Standard error of	0.024495923	0.022414001	0.095867262	0.037969257	0.017594255
Mean±SD	1.015±0.024	0.818±0.022	0.609±0.096	0.419±0.038	0.223±0.018

TABLE 2

TABLE 3

TABLE 4

TABLE 5

Figure3-A	Con	Zln	Cisp	C+Z
						1	1.064882	0.501576	0.6993696
	1.000001	1.116152	0.59	0.89198
						1.02	1.03	0.625637	0.807438
Mean value	1.006667	1.070344667	0.572404333	0.799595867
					Standard error of	0.011546717	0.043335001	0.063874788	0.096544372
Mean±SD	1.007±0.012	1.07±0.043	0.572±0.064	0.71±0.097

TABLE 6

Figure3-B	Con	Zln	Cisp	C+Z
					PGC-1α	1.007371	1.624646	0.622287	1.070257
	1.017666	1.248279	0.602322	0.866307
						0.999905	1.480735	0.736507	1.366842
Mean value	1.008314	1.45122	0.653705333	1.101135333
					Standard error of	0.008917972	0.189911509	0.072399843	0.251692124
Mean±SD	1.008±0.009	1.451±0.19	0.654±0.072	1.101±0.252

Bcl-2	1.107207	1.285348	0.686534	0.93589
						1.006624	1.300324	0.52379	0.843003
	1.050662	1.37225	0.721631	0.928416
					Mean value	1.054831	1.319307333	0.643985	0.902436333
Standard error of	0.050420932	0.046457127	0.10556078	0.051606259
					Mean±SD	1.055±0.05	1.319±0.046	0.644±0.106	0.902±0.052

					Bax	1.014936	0.861538	1.49049	0.893964
	1.033556	0.825439	1.853361	1.251797
						1.017631	0.889276	1.524971	0.82846
Mean value	1.022041	0.858751	1.622940667	0.991407
					Standard error of	0.010062911	0.032009626	0.200293241	0.227870375
Mean±SD	1.022±0.01	0.859±0.032	1.623±0.2	0.991±0.228

TABLE 7

TABLE 8

Figure4-A	NC	Zln	Cisp	C+Z
					BUN	28	27	312	84
	30	36	308	130
						32	40	138	150
	30	36	231	54
						21		234	153
	24		285	75
						27		198	45
Mean value	27.42857143	34.75	243.7142857	98.71428571
					Standard error of	3.823486317	5.5	63.27378153	45.12838828
Mean±SD	27.429±3.823	34.75±5.5	243.714±63.274	98.714±45.128

Crea	18	15	128	39
						21	24	154	42
	20	18	30	18
						18	18	96	95
	12		75	21
						12		132	60
	15		54	24
					Mean value	16.57142857	18.75	95.57142857	42.71428571
Standard error of	3.644957378	3.774917218	45.17321162	27.32345931
					Mean±SD	16.571±3.645	18.75±3.775	95.571±45.173	42.714±27.323

TABLE 9

Watch 10

Figure5-B	Con	Zln	Cisp	C+Z
						0.284464	0.426696	5.12035	2.130744
	0.828775	0.656455	5.073851	2.256565
						1.887309	0.218818	5.71663	2.789934
Mean value	1.000182667	0.433989667	5.303610333	2.392414333
					Standard error of	0.815054271	0.218909648	0.358440334	0.349963062
Mean±SD	1±0.815	0.434±0.22	5.304±0.358	2.392±0.35

TABLE 11

Figure5-D	Con	Zln	Cisp	C+Z
					Ndufs4	0.998805	0.941505	0.798112	0.893896
	1.00087621	0.960786	0.669913	0.93
						1.007556627	0.940622	0.770381	1.076269
Mean value	1.002412612	0.947637667	0.746135333	0.966721667
					Standard of meritError of	0.004573636	0.011395347	0.067450983	0.096572969
Mean±SD	1.002±0.005	0.948±0.011	0.746±0.067	0.967±0.097

ATP5b	1.08537	1.084522	0.803641	0.893897
						0.997958454	0.958249	0.675597	0.926
	1.007874925	1.113274	0.784553	1.08785
					Mean value	1.030401126	1.052015	0.754597	0.969249
Standard error of	0.047861957	0.082466456	0.069078491	0.103958158
					Mean±SD	1.03±0.048	1.052±0.082	0.755±0.069	0.969±0.104

TABLE 12

Figure5-E	Con	Zln	Cisp	C+Z
						0.99594	1.137721	0.726491	0.974748
	1.00404	1.145693	0.740899	0.986378
						1.012174	1.210756	0.465401	0.90592
Mean value	1.004051333	1.164723333	0.644263667	0.955682
					Standard error of	0.008117006	0.040064236	0.155067043	0.043485707
Mean±SD	1.004±0.008	1.165±0.04	0.644±0.155	0.956±0.043

Example 2ZLN005 study of activation of autophagy by Cisp in improving mitochondrial dysfunction in HK2 cells

First, the effect of ZLN005 on the level of autophagy of HK2 cells was explored by the autophagy inhibitor HCQ; subsequently, in the Cisp-induced HK2 cell model, intervention was performed with ZLN 005: WB detected changes in autophagy levels of HK2 cells, immunofluorescence detected co-localization of mitochondria and autophagosomes, and WB detected changes in autophagy-related proteins LC3 II and P62.

Detecting ZLN005 effect of 005 intervention on Cisp-induced HK2 mitochondrial dysfunction: the flow-type mitochondria ROS and WB detect the expression change of mitochondria-related proteins (ATP5b, Ndufs4), ATP detection and the like.

The results in FIG. 6 show that: in an AKI model of Cisp-induced HK2 cells, autophagy-related protein LC3 II is remarkably increased, and P62 is remarkably reduced; LC3 II was further increased after addition of the autophagy inhibitor HCQ, suggesting that Cisp can induce an increase in the level of autophagy by HK 2. ZLN005 following intervention further increased expression of autophagy marker protein LC3 II and significantly reduced Cisp-induced apoptosis. ZLN005 induced an increase in P62 in HK2 cells, which was associated with an increase in their transcription level.

ZLN005, the expression of the protein related to the mitophagy is obviously up-regulated under the intervention of the antigen, and LC3 and mitochondria are observed to be co-localized and increased by immunofluorescence, which indicates that ZLN005 possibly activates the mitophagy. In addition, ZLN005 significantly improved Cisp-induced HK2 mitochondrial function impairment as seen by mitochondrial ROS, membrane potential, ATP levels, mitochondrial morphology and WB detection of mitochondrial-associated protein results.

Watch 13

Figure6-B	Con	HCQ	Cisp	C+H
					LC3-II	1.007757	2.601391	1.74445	4.645133
	1.001798	2.578544	3.273204	6.749454
						0.998738	1.863763	1.383516	8.345008
Mean value	1.002764333	2.347899333	2.133723333	6.579865
					Standard error of	0.004586495	0.419429956	1.003185168	1.855758356
Mean±SD	1.003±0.005	2.35±0.419	2.134±1.003	6.58±1.856

P62	1.044455	1.819499	0.998823	1.547479
						1.055918	1.490154	0.782479	1.052327
	1.000449	1.511664	0.768597	1.165912
						1.00283	1.797172	0.933237	1.413504
Mean value	1.025913	1.65462225	0.870784	1.2948055
					Standard error of	0.028433232	0.177943475	0.113334782	0.226084489
Mean±SD	1.026±0.028	1.655±0.178	0.871±0.113	1.295±0.226

TABLE 14

Figure6-C	Con	Zln	Cisp	C+Z
					P62	1.007202	1.196402	0.66717	0.860225
	0.98723278	1.305503	0.697688	1.047792
						0.995349898	1.033158	0.485389	0.829339
Mean value	0.996594893	1.178354333	0.616749	0.912452
					Standard error of	0.010042656	0.137066548	0.114779895	0.118220865
Mean±SD	0.997±0.01	1.178±0.137	0.617±0.115	0.912±0.118

TFEB	1.097683	1.221211	0.715836	1.207961
						0.977484092	1.380025	0.586259	1.22964
	1.006188742	1.150948	0.750149175	1.089477
					Mean value	1.027118611	1.250728	0.684081392	1.175692667
Standard error of	0.062773314	0.117356329	0.086436472	0.075447668
					Mean±SD	1.027±0.063	1.251±0.117	0.684±0.086	1.176±0.075

					LC3-II	1.003323	1.078433	1.36904	1.690209
	1.109652468	1.525462	1.589289	1.780374
						1.025006121	1.583074	1.59025	2.02394
Mean value	1.045993863	1.395656333	1.516193	1.831507667
					Standard error of	0.056185878	0.276229557	0.127439142	0.17264149
Mean±SD	1.046±0.056	1.396±0.276	1.516±0.127	1.832±0.173

Watch 15

Figure6-D	Con	Zln
			Mean±SD	1±0.041	1.279±0.073

Example 3 study of TFEB-regulated autophagy in ZLN005 improvement of Cisp-induced mitochondrial dysfunction in HK2 cells

Through silencing the expression of TFEB of HK2 cells by RNA interference technology, comprehensively evaluating the autophagy, mitochondrial function, apoptosis and other capabilities of HK2 cells, and discussing whether ZLN005 relies on TFEB activation to remove damaged mitochondria for repairing Cisp-induced HK2 injury.

The results in FIG. 7 show that: the co-immunoprecipitation proves that interaction exists between PGC-1 alpha and TFEB, expression of PGC-1 alpha is activated by ZLN005, so that the expression level of TFEB can be up-regulated, autophagy is further promoted, and mitochondrial dysfunction induced by Cisp is improved. Upon silencing TFEB, ZLN005 abolished the improvement in Cisp-induced cell injury.

TABLE 16

TABLE 17

Watch 18

Watch 19

Watch 20

TABLE 21

Example 4 establishment of Cisp-induced mouse AKI model

Preparing a Cisp solution: and (4) preparing a Cisp solution by using physiological saline. C57BL/6 mice A single intraperitoneal injection of Cisp (16mg/kg) was used to establish the AKI mouse model. The materials are taken four days later, the blood biochemistry of the mouse is detected, the pathological change of the kidney tissue is detected through HE and PAS staining, and the autophagy level change of the kidney tissue of the mouse is detected through WB.

Biochemical detection results (shown in figure 1) show that creatinine and urea nitrogen levels are remarkably increased after four days of Cisp modeling, and HE and PAS results show that renal tubular epithelial cells are exfoliated, and large-area renal tubular necrosis is generated. The immunohistochemical result shows that the PGC-1 alpha expression content is obviously reduced and the renal tubular injury index Kim-1 expression is obviously increased in the AKI model group. WB results showed a significant increase in the pro-apoptotic protein Bax and a significant decrease in the anti-apoptotic protein Bcl2 in the AKI model group. The autophagy level detection of kidney tissues shows that the expression level of LC3 II is increased in the AKI model group compared with that in the NC group.

TABLE 22

Example 5 intervention of oral gavage ZLN005 on Cisp-induced AKI Damage in mice

The in vivo experiments in mice were divided into three groups: normal control group (NC), AKI model group (AKI), ZLN005 treatment group (Cisp + ZLN 005). ZLN005 preparation of solution: ZLN005 stock solution was made up in DMSO and then diluted with water buffer solution to a final DMSO concentration of no more than 1%. AKI mice were modeled using a single intraperitoneal injection of Cisp (16 mg/kg). ZLN005(15mg/kg, i.g.) intervention was started on the day of molding for 4 days, for a total of 4 treatments. And (3) killing mice on the 5 th day of model building, taking the materials, and detecting relevant indexes of blood biochemistry, pathological change, mitochondrial function detection by an electron microscope, autophagy detection by WB, apoptosis detection and the like of the mice.

Pathological and biochemical index detection shows that compared with AKI group, Cisp + ZLN005 group mice have obviously reduced pathological damage to kidney and obviously reduced levels of blood creatinine and urea nitrogen. Furthermore, the ZLN005 intervention significantly reduced the level of apoptosis in renal cells in AKI as demonstrated by the TUNNEL staining results and WB detection of apoptosis-related proteins (Bcl-2 and Bax). When WB is used for detecting the expression of autophagy-related proteins LC3 II and TFEB, the level of AKI group LC3 II is increased, but the level of TFEB is obviously reduced; ZLN005 the expression of LC3 II and TFEB was also increased after the prognosis of the prognosis, indicating that ZLN005 increased the level of renal autophagy in AKI mice. Detection of renal mitochondrial biological function: electron microscopy showed that tubular epithelial mitochondria in AKI mice were in a fragmented spherical shape, and mitochondria in ZLN005 treated groups were in an elliptical shape. In addition, ZLN005 intervention also significantly inhibited the reduction of kidney mitochondria-associated proteins (ATP5b and Ndufs4) in AKI mice. Meanwhile, the ROS level of kidney mitochondria in the AKI group is higher through detecting the ROS in fresh tissue frozen sections, and the ROS level of mitochondria is reduced after ZLN005 drying.

TABLE 23

Watch 24

Figure8-C	NC	Cisp	C+Z
				ATP5b	0.91101	0.721751	1.097883
	1.042317	0.765447	1.017068
					1.046673	0.69028	0.698434
Mean value	1	0.725826	0.937795
				Standard error of	0.077098371	0.037748824	0.2111943
Mean±SD	1±0.077	0.726±0.038	0.938±0.21

Ndufs4	0.926939	0.648424	0.758758
					1.132435	0.453867	0.6384
	0.940627	0.523738	0.573022
				Mean value	1.000000333	0.542009667	0.656726667
Standard error of	0.114895805	0.098557074	0.094214465
				Mean±SD	1±0.115	0.542±0.099	0.657±0.094

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

Use of overexpression of PGC-1 α for the preparation of a medicament for the treatment and/or prevention of kidney disease.
Use of a PGC-1 alpha transcription modulator for the preparation of a medicament for the treatment and/or prevention of renal disease.
3. The use of claim 2, wherein the PGC-1 α transcriptional modulator comprises ZLN005(2- (4-tert-butylphenyl) benzimidazole).
4. The use of claim 2 or 3, wherein the transcriptional modulator of PGC-1 α further activates TFEB-mediated clearance of damaged mitochondria by activating the transcriptional level of PGC-1 α.
5. The use according to any one of claims 2 to 4, wherein the transcriptional modulator of PGC-1 α is capable of ameliorating mitochondrial dysfunction in renal tubular epithelial cells.
6. The use of any one of claims 2 to 5, wherein the renal disease comprises Cisp-induced acute kidney injury.
7. The medicine for treating and/or preventing kidney diseases is characterized by comprising a PGC-1 alpha transcription regulator and pharmaceutically acceptable auxiliary materials.
8. The pharmaceutical of claim 7, wherein said transcriptional modulator of PGC-1 α comprises ZLN005(2- (4-tert-butylphenyl) benzimidazole).
9. A medicament as claimed in claim 7 or claim 8, wherein the renal disease comprises Cisp-induced acute kidney injury.