ACE2/Ang（1-7）/Mas轴对尿毒症大鼠高转化骨病的改善作用

doi:10.13481/j.1671-587X.20250104

Abstract

Abstract:

Objective To discuss the effect of angiotensin （1-7）［Ang（1-7）］ on high-turnover bone disease in the uremic rats， and to clarify its possible mechanism. Methods Thirty SD rats were randomly divided into sham operation group（n=6） and experimental group（n=24）. The rats in experimental group underwent 5/6 nephrectomy（Platt method） + high-phosphorus（P） diet［1.2% P， 1.0% calcium（Ca）］ to establish the model of uremic high-turnover bone disease. The successfully modeled rats were then randomly divided into model group， Ang（1-7） group， angiotensin-converting enzyme 2（ACE2） activator dimethylacetamide amidoxime（DIZE） group， and Mas receptor antagonist group （A779 group）， with 6 rats in each group. The levels of Ca， P， blood creatinine （Scr）， blood urea nitrogen （BUN）， and 24 h urinary protein （UP） in serum of the rats in various groups were detected by automatic biochemical analyzer at 12 and 18 weeks after operation； immunofluorescence staining was used to detect the levels of intact parathyroid hormone （iPTH） in the rats in various groups； ELISA method was used to detect the levels of osteocalcin（OC）， type Ⅰ collagen N-terminal peptide （NTX）， and tartrate-resistant acid phosphatase （TRAP）-5b in serum of the rats in various groups； high-resolution micro-CT scan was used to detect the bone density （BMD）， tissue mineral density （TMD）， trabecular thickness （Tb.Th）， and trabecular separation （Tb.Sp） in femur tissue of the rats in various groups； Von Kossa staining and Giemsa staining were used to observe the pathomorphology of cortical bone and trabecular bone of the rats in various groups， and the trabecular bone volume （TBV） was calculated； fluorescence microscope was used to detect the mineral apposition rates （MAR） of the rats in vanious groups， and the osteoblast index （OBI） and osteoclast index （OCI） of the rats in various groups were calculated. Results At 12 and 18 weeks after operation， compared with sham operation group， the weights of the rats in model group， Ang（1-7） group， DIZE group， and A779 group were decreased （P<0.05）. At 12 and 18 weeks after operation， compared with sham operation group， the levels of 24 h UP， Scr， and BUN in serum of the rats in model group， Ang（1-7） group， DIZE group， and A779 group were increased （P<0.05）； at 18 weeks after operation， compared with model group， the levels of 24 h UP and Scr in serum of the rats in Ang（1-7） group and DIZZ group were decreased （P<0.05）， and the levels of 24 h UP， Scr and BUN in serum of the rats in A779 group were increased （P<0.05）. The successful establishment of the uremic high-turnover bone disease model was confirmed. At 12 and 18 weeks after operation， compared with sham operation group， the serum iPTH， P， OC， NTX， and TRAP-5b levels of the rats in model group， Ang（1-7） group， DIZE group， and A779 group were all significantly increased （P<0.05）； at 18 weeks after operation， compared with model group， the serum NTX and TRAP-5b levels of the rats in Ang（1-7） group and DIZE group were decreased（P<0.05）， while the serum iPTH， P， NTX and TRAP-5b levels in A779 group were increased（P<0.05）. The high-resolution micro-CT scan results showed that compared with sham operation group， the values of femur BMD and TMD of the rats in model group， Ang（1-7） group， DIZE group， and A779 group were all significantly decreased （P<0.05）； compared with model group， the values of femur BMD and TMD of the rats in Ang（1-7） group and DIZE group were increased （P<0.05）， while the values of BMD and TMD of the rats in A779 group were decreased （P<0.05）. Compared with sham operation group， the femur Tb.Th of the rats in model group was decreased （P<0.05）， and the Tb.Sp was increased （P<0.05）； the femur Tb.Th of the rats in Ang（1-7） group and DIZE group were increased （P<0.05）， and the Tb.Sp was decreased （P<0.05）. Compared with model group， the femur Tb.Th of the rats in A779 group was decreased （P<0.05）， and the Tb.Sp was increased （P<0.05）. The bone pathological examination results showed that compared with sham operation group， the femur TBV of the rats in model group， Ang（1-7） group， DIZZ group and A779 group were decreased （P<0.05）， and MAR， OBI and OCI were increased （P<0.05）； compared with model group， the OBI and OCI of the rats in Ang（1-7） group and DIZE group were decreased （P<0.05）， and TBV was increased （P<0.05）， while the OBI and OCI of the rats in A779 group were increased （P<0.05）， and TBV was decreased （P<0.05）. Conclusion The ACE2/Ang（1-7）/Mas axis improves high-turnover bone disease in the uremic rats.

Key words: Uremia, High-turnover bone disease, Osteoblasts, Osteoclasts, Angiotensin-converting enzyme 2, Angiotensin （1-7）

CLC Number:

R563.13

Yang XUE,Yingxin RUAN,Tiekun YAN,Junya JIA,Shan LIN. Ameliorative effect of ACE2/Ang（1-7）/Mas axis on high-turover bone disease in uremic rats[J].Journal of Jilin University(Medicine Edition), 2025, 51(1): 26-33.

Figures/Tables 6

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References 25

1	朱家恺. 外科学辞典［M］. 北京：北京科学技术出版社， 2003.
2	KANEKO K， ITO M， FUMOTO T， et al. Physiological function of the angiotensin AT1a receptor in bone remodeling［J］. J Bone Miner Res， 2011， 26（12）： 2959-2966.
3	SPERETTA G F， RUCHAYA P J， DELBIN M A， et al. Importance of AT1 and AT2 receptors in the nucleus of the solitary tract in cardiovascular responses induced by a high-fat diet［J］. Hypertens Res， 2019， 42（4）： 439-449.
4	黎秀芝，尹新华. ACE2/Ang（1-7）/Mas轴在心血管疾病中的研究进展［J］. 医学综述， 2020， 26（20）： 3969-3975.
5	BAYOMY O， ZAHEER S， WILLIAMS J S， et al. Disentangling the relationships between the renin-angiotensin-aldosterone system， calcium physiology， and risk for kidney stones［J］. J Clin Endocrinol Metab， 2020， 105（6）： 1937-1946.
6	HATTON R， STIMPEL M， CHAMBERS T J. Angiotensin Ⅱ is generated from angiotensin Ⅰ by bone cells and stimulates osteoclastic bone resorption in vitro［J］. J Endocrinol， 1997， 152（1）： 5-10.
7	樊长萍，侯建明. 原发性醛固酮增多症与骨质疏松症的相关性［J］. 中华骨质疏松和骨矿盐疾病杂志， 2016， 9（2）： 199-204.
8	SALAM S， GALLAGHER O， HUGHES D， et al. The role of static bone histomorphometry in diagnosing renal osteodystrophy［J］. Bone， 2021， 142： 115689.
9	FERREIRA A C， COHEN-SOLAL M， D’HAESE P C， et al. The Role of Bone Biopsy in the Management of CKD-MBD［J］. Calcif Tissue Int， 2021，108（4）：528-538.
10	JØRGENSEN H S， BEHETS G， VIAENE L， et al. Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels［J］. Bone， 2021， 152： 116066.
11	李红芬，林珊，贾俊亚，等. 长期低剂量1α，25-二羟基维生素D3对尿毒症大鼠肾脏水通道蛋白2表达的影响［J］. 中华肾脏病杂志， 2013， 29（2）： 124-128.
12	祝再然，林珊，贾俊亚，等. 长期接受不同饮食磷水平的慢性肾衰竭大骨组织形态学特征改变［J］. 北京医学， 2011， 33（2）： 167-169.
13	PAZIANAS M， MILLER P D. Osteoporosis and chronic kidney disease-mineral and bone disorder（CKD-MBD）： back to basics［J］. Am J Kidney Dis， 2021， 78（4）： 582-589.
14	TSUJI K， KITAMURA M， CHIBA K， et al. Comparison of bone microstructures via high-resolution peripheral quantitative computed tomography in patients with different stages of chronic kidney disease before and after starting hemodialysis［J］. Ren Fail， 2022， 44（1）： 381-391.
15	NEYRA J A， HU M C， MOE O W. Klotho in clinical nephrology： diagnostic and therapeutic implications［J］. Clin J Am Soc Nephrol， 2020， 16（1）： 162-176.
16	SAAR-KOVROV V， DONNERS M M P C， VAN DER VORST E P C. Shedding of klotho： functional implications in chronic kidney disease and associated vascular disease［J］. Front Cardiovasc Med， 2021， 7： 617842.
17	程虹. 中晚期慢性肾脏病患者血管钙化管理［J］. 中国实用内科杂志， 2023， 43（3）： 218-224.
18	汤曦，石运莹，王俭勤，等. 中国成人慢性肾脏病及其并发症早期筛查临床路径专家建议（2023版）［J］. 中国实用内科杂志， 2023， 43（3）： 198-205.
19	KONO K， FUJII H， WATANABE K. Relationship between parathyroid hormone and renin-angiotensin-aldosterone system in hemodialysis patients with secondary hyperparathyroidism［J］. J Bone Miner Metab， 2021， 39（2）： 230-236.
20	WANG Y L， MA W X， PU J H， et al. Interrelationships between sarcopenia， bone turnover markers and low bone mineral density in patients on hemodialysis［J］. Ren Fail， 2023， 45（1）： 2200846.
21	PARK S Y， AHN S H， YOO J I， et al. Position statement on the use of bone turnover markers for osteoporosis treatment［J］. J Bone Metab， 2019， 26（4）： 213-224.
22	WU J， WANG M， GUO M， et al. Angiotensin receptor blocker is associated with a lower fracture risk： an updated systematic review and meta-analysis［J］. Int J Clin Pract， 2022， 2022： 7581110.
23	QUEIROZ-JUNIOR C M， SANTOS A C P M， GALVÃO I， et al. The angiotensin converting enzyme 2/angiotensin-（1-7）/Mas Receptor axis as a key player in alveolar bone remodeling［J］. Bone， 2019， 128： 115041.
24	章海涛. 新型盐皮质激素受体拮抗剂的临床应用［J］. 肾脏病与透析肾移植杂志， 2021，30（5）： 449-450.
25	TIWARI P， TIWARI V， GUPTA S， et al.Activation of angiotensin-converting enzyme 2 protects against lipopolysaccharide-induced glial activation by modulating angiotensin-converting enzyme 2/angiotensin（1-7）/mas receptor axis［J］. Mol Neurobiol，2023， 60（1）： 203-227.

Group	Body weight（m/g）		24 h UP（mg·d^－1）		Scr[c_B/（μmol·L^－1）]		BUN[c_B/（mmol·L^－1）]
Group	(week)12	18	12	18	12	18	12	18
Sham operation	156±12	149±17	8±1	7±2	66±34	69±36	5±1	6±1
Model	128±21^*	119±25^*	52±12^*	67±29^*#	94±12^*	170±37^*#	15±3^*	26±7^*#
Ang（1-7）	122±27^*	118±16^*	58±18^*	60±26^*△	92±21^*	110±27^*△	16±1^*	18±5^*△#
DIZE	115±22^*	121±18^*	48±15^*	62±14^*△#	97±26^*	116±35^*△	16±5^*	22±7^*△#
A779	112±25^*	114±23^*	62±10^*	74±25^*△#	99±17^*	230±32^*△#	17±2^*	29±11^*△#

Group	iPTH[c_B/（pmol·L^－1）]		Ca[c_B/（mmol·L^－1）]		P[c_B/（mmol·L^－1）]
Group	（week）12	18	12	18	12	18
Sham operation	35±7	34±12	2.3±0.3	2.3±0.1	1.3±0.1	1.3±0.1
Model	67±21^*	102±16^*#	2.4±0.1	2.3±0.2	2.6±0.1^*	2.6±0.4^*
Ang（1-7）	70±21^*	95±20^*#	2.2±0.2	2.3±0.1	2.2±0.5^*	2.3±0.2^*
DIZE	66±19^*	101±32^*	2.2±0.3	2.3±0.2	2.5±0.2^*	2.6±0.1^*
A779	76±24^*	108±21^*△#	2.4±0.3	2.4±0.1	2.5±0.1^*	2.8±0.5^*△#

Group	OC [ρ_B/（μg·L^－1）]		NTX [c_B/（nmol·L^－1）]		TRAP-5b [λ_B/（U·L^－1）]
Group	（week） 12	18	12	18	12	18
Sham operation	1.3±0.1	1.4±0.1	33±12	36±16	3.6±0.4	5.4±1.9
Model	2.1±0.3^*	2.4±0.3^*	89±22^*	111±25^*#	10.4±1.1^*	10.6±1.2^*
Ang（1-7）	2.3±0.3^*	2.3±0.3^*	83±17^*	85±31^*△	8.4±0.3^*△	8.3±0.7^*△
DIZE	2.2±0.1^*	2.3±0.2^*	96±19^*	98±11^*△	8.2±3.3^*△	8.5±1.2^*△
A779	2.3±0.3^*	2.3±0.3^*	85±16^*	128±29^*△#	10.0±1.7^*△	12.4±3.6^*△#

Group	BMD（g·cm^-3）	TMD（mgHA·cm^-3）	Tb.Th(l/μm)	Tb.Sp(l/μm)
Sham operation	210±82	891±125	7.6±1.2	6.5±1.2
Model	101±32^*	320±128^*	3.9±0.3^*	11.3±2.3^*
Ang（1-7）	189±72^*△	710±201^*△	5.5±2.1^*△	6.5±1.0^*△
DIZE	185±56^*△	810±138^*△	5.9±2.0^*△	7.5±1.0^*△
A779	62±10^*△	271±22^*△	3.1±1.0^*△	13.5±1.0^*△

Group	TBV （η/%）	MAR （μm·d^－1）	OBI （η/%）	OCI （η/%）
Sham operation	8.0±3.2	1.9±0.6	17.5±6.1	8.1±2.1
Model	6.6±1.2^*	5.3±2.1^*	25.1±5.4^*	14.3±4.4^*
Ang（1-7）	7.0±2.1^*△	5.7±3.8^*	20.8±5.0^*△	9.1±2.7^△
DIZE	7.3±2.2^*△	5.2±1.9^*	18.2±3.9^*△	9.2±3.3^△
A779	6.1±1.3^*△	5.9±0.1^*	35.5±6.1^*△	23.1±8.1^*△

Ameliorative effect of ACE2/Ang（1-7）/Mas axis on high-turover bone disease in uremic rats

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