早期生命編程：雷尼-安基奧特辛系統與心血管-腎臟-代謝綜合徵的關聯

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本研究探討了雷尼-安基奧特辛系統（RAS）在心血管-腎臟-代謝（CKM）綜合徵中的角色，強調早期生命編程的影響。研究指出，母體在妊娠和哺乳期間RAS的失調可能導致後代出現CKM特徵。這一綜述整合了目前的前臨床證據，並提出針對RAS的干預措施，旨在改善心血管和腎臟健康結果，促進臨床轉化。

The Renin-Angiotensin System and Cardiovascular-Kidney-Metabolic Syndrome: Focus on Early-Life Programming

腎素–血管緊張素系統與心血管–腎臟–代謝症候群：聚焦於生命早期的編程

Tain YL, Hsu CN. The Renin-Angiotensin System and Cardiovascular-Kidney-Metabolic Syndrome: Focus on Early-Life Programming. Int J Mol Sci. 2024;25(6):3298. Published 2024 Mar 14. doi:10.3390/ijms25063298

https://pubmed.ncbi.nlm.nih.gov/38542273/

Abstract

摘要

代謝失調、腎臟疾病與心血管疾病之間的病理聯結，催生了心血管–腎臟–代謝（CKM）症候群的概念。新出現的產前風險因素似乎增加了個體一生中罹患CKM症候群的可能性。腎素–血管緊張素系統（RAS）在維持母胎健康及心血管、代謝與腎臟功能的平衡中扮演關鍵角色。本綜述匯總了現有的臨床前證據，詳細說明了懷孕及哺乳期間RAS失調如何導致後代出現CKM特徵，並闡明了其潛在機制。RAS的多器官效應，對胎兒編程的影響以及觸發後代CKM症狀，顯示其作為潛在重編程策略的可能性。此外，我們概述了針對RAS的干預措施，以預防CKM特徵。本綜合評述旨在促進RAS在CKM症候群早期生命編程中的臨床轉化過程，最終改善心血管–腎臟–代謝健康的預後。

關鍵詞：心血管疾病；慢性腎病；代謝症候群；腎素–血管緊張素系統；肥胖；高血壓；健康與疾病發展起源（DOHaD）；血管緊張素轉化酶

引言

隨著對代謝風險因素（如肥胖與糖尿病）、心血管疾病（CVD）及慢性腎臟病（CKD）之間病理聯結的逐步認識，心血管–腎臟–代謝（CKM）症候群的概念應運而生【1】。在2023年的科學聲明中，美國心臟協會首次將CKM症候群定義為一種全身性疾病，其特徵在於代謝風險因素、CKD與心血管系統之間的複雜病理交互作用。這些相互作用導致多器官功能障礙，並提高了心血管和腎臟不良結果的風險【1】。CKM症候群被劃分為四個階段，從第0階段到第4階段。這些階段被認為涵蓋了該症候群在不同程度上的進展與強度，各階段出現的關鍵因素影響了CKM症候群在不同複雜程度上的發展與嚴重性。
據估計，美國約有40%的成年人受到CKM症候群的影響【2】。由於其導致多器官功能障礙，全球心血管–腎臟–代謝健康的負擔顯著增加。雖然建議透過整體方法來管理這種症候群，針對整體而非單一疾病進行處理【2】，但目前仍缺乏具體的治療指南。值得強調的是，早期預防優先的重要性在於能減輕與CKM症候群相關的負擔。理解CKM疾病之間的相互聯繫，對於採取更全面的CKM護理方式至關重要，這種方式超越了單一疾病的孤立治療，並展現出改善全球健康結果的潛力。

目前已普遍接受許多成年慢性病的風險可能源於生命早期【3,4】。發育過程中若經歷次優的子宮內環境，會對結構與功能以及補償機制產生持續性的負面影響，這一現象被稱為發展性編程，或稱「健康與疾病的發展起源」（DOHaD）【5】。DOHaD理論提出了早期生命編程與CKM症候群若干已知組成部分之間的聯繫，涵蓋了代謝疾病【6】、慢性腎臟病（CKD）【7】、心血管疾病（CVD）【8】、高血壓【9】及肥胖【10】。相反地，該理論促使治療策略發生了理論轉變，將重點從成年後的疾病治療轉移至更早期的干預，即進行重編程，旨在潛在逆轉疾病過程，防止其臨床表現【11,12】。

與CKM症候群發展性編程相關的各種分子機制已被深入探討。這些機制包括腎素–血管緊張素系統（RAS）發育不全、一氧化氮（NO）缺乏、表觀遺傳調控、氧化壓力、營養感應信號的中斷、腎元數量減少及腸道菌群失衡【11,12,13,14,15,16,17】。在這些機制中，RAS作為一個核心樞紐，與其他因素緊密聯繫，共同影響不利的編程過程。

RAS作為一個激素級聯反應，首先由血管緊張素原（AGT）的表達開始，該分子經由腎素酶轉化為血管緊張素I（Ang I）。隨後，血管緊張素轉化酶（ACE）將Ang I轉化為血管緊張素II（Ang II）【18】。RAS在協調心血管系統、腎臟及代謝穩態的多種生理功能中發揮關鍵作用【19,20】。相反，Ang II透過經典RAS途徑的激活，包括ACE、Ang II及Ang II 1型受體（AT1R），經常引發血管收縮與細胞增生等病理效應，這些效應在CKM症候群中促成了高血壓、CKD、肥胖、肝臟脂肪變性及糖尿病等病症【20,21,22,23,24】。另一方面，非經典的RAS途徑，涉及ACE2-ANG-(1-7)-MAS受體軸，則用以抵消Ang II信號的有害效應【25】。

在此框架下，RAS成為理解與預防具有發展起源的CKM症候群的關鍵焦點。經典RAS的抑制或非經典RAS的促進構成了現有心臟保護、抗高血壓、腎臟保護及抗肥胖療法的依據【18,25,26,27,28】。雖然目前有關早期針對RAS的干預是否能預防後代CKM症候群的資料有限，但本綜述的目的是探討RAS與CKM症候群發展性編程之間的機制性聯繫。我們通過科學數據庫如SCOPUS、Embase、MEDLINE及Cochrane資料庫，總結了RAS、發展性編程與CKM症候群之間的關係，涵蓋了分子機制，並確定了可能針對RAS進行重編程的干預措施，以預防CKM症候群。我們的檢索使用了關鍵詞及其組合，如「高血壓」、「慢性腎臟病」、「肥胖」、「代謝症候群」、「糖尿病」、「高血脂」、「心血管疾病」、「發展性編程」、「DOHaD」、「後代」、「母親」、「腎元」、「懷孕」、「妊娠」、「哺乳」、「子代」、「重編程」、「腎素受體」、「醛固酮」、「礦物皮質激素受體」、「血管緊張素原」、「血管緊張素轉化酶」、「腎素」及「血管緊張素」。我們還選擇並評估了相關文獻中的補充研究，最終檢索於2024年1月30日完成

系統性與局部RAS

腎素是啟動RAS級聯反應的關鍵，其前體腎素原（406個胺基酸）【29】僅在腎臟中進行蛋白水解，腎素與腎素原一同被分泌到循環系統中【30】。腎素（340個胺基酸）作為一種激素【31】，與由Atp6ap2編碼的（腎素）受體（PRR）結合【32】。循環中的腎素與腎素原與PRR的相互作用，觸發了不依賴Ang II的信號級聯，啟動了局部Ang II的生成。
RAS的底物血管緊張素原（AGT）由肝臟釋放，經由腎素裂解產生Ang I。血管緊張素轉化酶（ACE）進一步裂解Ang I，形成Ang II，分佈於各組織中【33】。當Ang II刺激AT1R時，鈉的重吸收增加，血壓上升；而AT2R則促進血管擴張並降低血壓【34】。Ang II還促進脂肪生成【35】，增加脂肪組織質量，並刺激腎上腺皮質分泌醛固酮，維持鈉鉀平衡。腎臟的RAS具有最高濃度的Ang II，涉及Ang II向Ang III與Ang IV的代謝【36】。

ACE2將Ang II轉化為Ang-(1-7)或將Ang I轉化為Ang-(1-9)。Ang-(1-7)經由MAS受體作用，誘導利鈉與利尿效應，促進血管擴張【37】。中性內肽酶（NEP）促進Ang I轉化為Ang-(1-7)，隨後的代謝過程產生Ang-(2-7)及Ang-(3-7)。

由於系統性與局部RAS之間有大量重疊，區分兩者存在挑戰【38】。局部脂肪RAS在脂肪組織中表達，調節脂肪生成、脂肪合成、脂解及炎症等過程【39】。腎臟擁有一個獨立的局部血管RAS，用於自主調節腎血管化。腎臟內一個獨特的尿RAS協調鈉的重吸收【40】。

若要全面理解RAS肽網絡對胎兒編程的影響，必須認識到不同肽之間的協作或對立特性。藥理學上的修正會引發RAS酶的補償性調整，這需要進一步研究以解開此網絡的複雜性及其對胎兒編程的影響，如圖1所示。

CKM症候群引發RAS紊亂

長期以來，內皮細胞被認為參與了血管穩態的調節【41】。血管內皮功能主要依靠內皮舒張因子（如一氧化氮，NO）與內皮收縮因子（如Ang II或超氧陰離子）之間的平衡來維持【42】。內皮功能障礙的特徵是血管收縮、促黏附、促凝血、細胞增生及促炎環境，這些因素導致動脈粥樣硬化，成為心血管疾病（CVD）發展的初始事件【42】。具體來說，在高血壓中，內皮功能障礙導致NO的可用性減少，進而損害了內皮依賴性的血管舒張【43】。
內皮功能障礙可由PRR的活化及隨之而來的高Ang II活性所引發【44】。腎素可能透過多種途徑與PRR相互作用，對CVD產生影響【45】，包括促進Ang I生成，從而增強RAS【46】，激活絲裂原活化蛋白激酶（MAPK）信號通路【47】，以及與V-ATPase關聯，暗示其具非RAS相關的功能【48】，並調節Wnt/β-連環蛋白信號通路【49】。其他研究指出，PRR在心肌細胞中的活化可能促進心肌缺血再灌注損傷、心肌肥大、糖尿病性心肌病、鹽誘發的心臟損傷及心力衰竭【49】。

Ang II衍生的超氧化物被公認為Ang II的經典效應中的重要信號成分【50】。對心血管系統影響最大的超氧化物來源為還原型煙酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶。NADPH氧化酶衍生的超氧化物介導了Ang II的多項作用，包括血管平滑肌的收縮、內皮功能障礙、血壓升高、血管重塑及鈉滯留【50】。此外，Ang II透過AT1R的激活引發血管收縮並增強交感神經系統的活性，進而升高血壓及醛固酮分泌，並造成心肌肥大及纖維化【51】。

在腎臟發育過程中，RAS的各組成部分高度表達，並在協調正確的腎臟結構及生理功能中起關鍵作用【52】。以大鼠為例，從妊娠第12至17天的胚胎腎臟中可檢測到所有RAS組成部分，且胎鼠和新生大鼠中的表達水平高於成年大鼠【53】。在人類研究中，干擾RAS的藥物如ACE抑制劑（ACEIs）或血管緊張素受體阻滯劑（ARBs）在孕婦中被刻意避免使用，原因是它們可能導致腎臟畸形及ACEI/ARB胎病的風險【54】。缺乏RAS基因的動物表現出顯著的腎臟發育不全【55,56】。在腎元生成階段阻斷RAS會導致腎元數量減少，並在成年期引發高血壓【57】。

在人類腎臟活檢中，RAS組成部分的表達與腎臟疾病的存在及嚴重程度呈現相關【58,59】。同樣，在多種CKD動物模型中，包括鏈脲佐菌素（STZ）誘導的糖尿病性腎病【60】、5/6腎切除/梗死模型【61】及腺嘌呤誘導的CKD【62】，均觀察到腎臟系統中經典RAS組成部分的上升。在腎臟中，間質空間的Ang II濃度極高。局部生成的Ang II可深刻影響腎臟功能，通過改變腎小球血流動力學、減少鈉的排泄及收縮小動脈來發揮作用【63】。此外，RAS的過度活性會引導促炎及促纖維化因子對腎臟造成損害【64】，而抑制RAS則在緩解腎臟纖維化方面顯示出療效【65】。

大多數RAS成分已被發現在脂肪組織中表達【66】。這一局部脂肪RAS在系統性及脂肪組織環境中，通過調節脂肪生成、脂肪合成、脂解及炎症等過程，發揮著重要的自分泌/旁分泌作用【66】。

在肥胖的情況下，經典RAS被激活，導致脂肪生成增加、脂解減少，並促進脂肪細胞的生長與分化。這些過程與肥胖、胰島素抵抗及炎症密切相關。隨後增加的脂肪質量進一步擾亂了血壓、血糖及血脂水平。因此，肥胖成為了2型糖尿病、CVD及腎臟疾病發展的風險因素，形成CKM症候群中病理聯結的惡性循環【67】。相反，非經典RAS軸的強化有助於改善血脂、胰島素抵抗、減少炎症及降低肥胖【68】。

Ang II誘導的氧化壓力增加、炎症及遊離脂肪酸水平上升，會導致糖尿病中的β細胞功能障礙【69】。許多器官參與了葡萄糖穩態的調節，包括胰臟、脂肪組織、骨骼肌及肝臟。這些器官中均已發現局部RAS的存在，且其活化與糖尿病的病理有關【70】。

此外，RAS的活化似乎增強了其他致病途徑的作用，包括糖毒性、脂毒性及晚期糖基化，這些均導致高血糖及胰島素抵抗【70】。在2型糖尿病的實驗模型中，抑制經典RAS或激活非經典RAS，顯示出了改善胰島結構與功能的效果【71,72,73】。

非酒精性脂肪肝病（NAFLD）是代謝失調的結果，包括肥胖、胰島素抵抗及代謝症候群。血脂異常在NAFLD的發展中扮演了關鍵角色。肝細胞內的游離脂肪酸及脂質代謝物會破壞胰島素引發的細胞信號，導致NAFLD的發生【74】。

高血糖、高膽固醇血症及胰島素抵抗會上調RAS的組成部分【75,76】。RAS的活化及其在肝組織中的表達促進了肝臟脂肪酸代謝、炎症及纖維化【77】。相反地，多項研究表明，ARBs對於改善血脂異常【74】及NAFLD具有正面效果【78】。

如本綜述所述，RAS與心血管疾病、腎臟疾病及代謝失調之間的複雜聯繫顯而易見。生命早期暴露於不利的環境因素可能會引發異常的RAS活化，最終導致後期CKM症候群的發生（圖2）。

懷孕中的RAS

腎素–血管緊張素系統（RAS）對孕婦和胎兒的心血管及腎臟發育有著重要影響。在健康的妊娠期間，血壓通常保持較低水平，而血漿腎素活性和醛固酮水平則維持在較高狀態，直到懷孕晚期，血壓才會上升【79】。Ang II誘導的醛固酮濃度升高，直接刺激腎臟鈉和液體的滯留，從而增加血液容量。在懷孕期間，胎兒循環中主要存在的ACE源自內皮細胞，其主要功能包括支持血管生成及確保胎兒灌流的維持【80】。懷孕還會激活非經典RAS途徑，以平衡增強的Ang II信號通路。這種適應性有助於母體血流動力學調整、胎盤功能及血管重塑【81】。在胎兒腎臟中，RAS對於腎臟結構的正常形成及生理功能的維持至關重要【52,53】。
在面臨挑戰的妊娠中，RAS可能對胎兒和母體的心血管及腎臟健康產生負面影響。在胎兒生長受限（IUGR）、子癇前症及妊娠糖尿病等妊娠併發症中，觀察到血漿PRR水平升高【82】。在胎盤功能不全導致IUGR的大鼠模型中，與新生大鼠的腎內RAS活性降低相關聯【83】。女性子癇前症與針對AT1R的循環自體抗體水平升高有關，這促進了血管收縮、高血壓及凝血功能增加【84】。RAS活化也與早產【85】、妊娠糖尿病【86】及妊娠高血壓【87】等不良結果有關。相反，在子癇前症【88】、早產【89】及妊娠糖尿病【90】等情況下，孕婦體內的Ang-(1-7)水平均減少。因此，這些RAS組成部分可能會引發心血管及腎臟功能的神經激素調節的二次變化，進而編程出高血壓、腎臟疾病及心血管疾病（CVD）【91】。然而，這些RAS變化的具體時間點及其對後續CKM症候群發展的重要性仍不明確。

動物模型中的RAS相關編程

表1概述了在其後代中表現出至少兩個CKM症候群組成部分的動物模型，特別是那些與異常RAS變化有關的模型【92-133】。為研究CKM症候群的具體方面，包括高血壓【12,134】、代謝症候群【135】、腎臟疾病【13】及CVD【15】，已開發了多種採用不同環境壓力的動物模型。儘管這些模型集中於誘發CKM症候群的特定組成部分，但尚無模型能夠完全複製與CKM症候群相關的所有特徵。

在最常見的模型中，母體營養不平衡的模型尤為突出（見表1）。這些模型涉及在懷孕和/或哺乳期間的特定營養操控，包括熱量限制、蛋白質限制、高果糖消費和高脂飲食。由於人類腎臟發育在足月出生時已完成，因此大多數臨床前模型針對動物在出生後腎臟發育持續的等效時間段。例如，在囓齒類動物中，腎臟發育在出生後持續1-2週。這種方法使研究人員能夠探索在器官發生期間的暴露對腎臟和心血管系統長期健康的影響。

孕期的蛋白質限制會導致後代的高血壓、胰島素抵抗和腎臟疾病，這些與RAS編程效應有關。研究發現，接受低蛋白飲食的母鼠所生的4週齡後代，其腎臟AT1R表達增加，AT2R表達減少【96】。

母體高果糖飲食會使雄性大鼠後代的血壓增加，並提高腎臟雷尼和腦AT1R的表達【101,102,103】。在一項特定研究中觀察到，母體高果糖飲食可能導致RAS的多代激活【102】。研究顯示，與對照組相比，第一代和第二代後代的血壓顯著升高，儘管在第三代和第四代中未觀察到此效應。第三代後代的血清雷尼、Ang II和醛固酮水平最高。此外，這種飲食模式導致了第一代至第三代大鼠後代腎臟中與RAS相關基因的mRNA表達增加【102】。

高脂飲食在動物模型中持續顯示與肥胖和相關疾病的出現有關【136,137】。目前的證據表明，暴露於母體高脂飲食的後代表現出CKM綜合徵的各種特徵【104,105,106,107】，包括肥胖、高血壓、胰島素抵抗、脂質異常和腎臟疾病。由母體高脂飲食引發的後代高血壓與經典RAS的異常激活有關。這表現在AGT和ACE的腎臟mRNA表達上升，以及AT1R蛋白水平增加【104】。另一項研究顯示，在16週齡的雄性後代中，母體接觸高脂飲食後，其腎臟中的Ang-(1-7)水準顯著降低【105】。

在妊娠期間，母體疾病和狀況可能對胎兒編程產生重大影響，增加後代發展CKM綜合徵的風險。因此，已建立模仿母體疾病和狀況的動物模型，以研究CKM綜合徵的不同方面，包括高血壓、肥胖、胰島素抵抗、脂質異常和腎臟疾病（參見表1）。母體疾病和狀況的範疇包括母體糖尿病【108,109,110】、慢性腎病（CKD）【111,112】、子宮胎盤功能不全【113,114,115】和母體缺氧【116,117】。

接受鏈脲佐菌素（STZ）處理的糖尿病母鼠所生的後代顯示出高血壓、肥胖、胰島素抵抗、脂質異常和腎臟疾病【108,109,110】。母體糖尿病導致後代腎臟中ACE和AT1R上調，並伴隨ACE2表達下調【108】。此外，母體糖尿病還導致後代高血壓，並伴隨ACE活性升高【109】。

接受腺嘌呤誘導的CKD母親的成年後代顯示高血壓和腎臟肥大。這些效應與AGT、雷尼、PRR、ACE和AT1R的腎臟基因表達上調，以及AT2R和MAS的下調相關【111,112】。母體子宮胎盤功能不全的模型作為生長受限（IUGR）的模型，隨後發展出高血壓、脂質異常、胰島素抵抗和腎臟疾病【83,113,114,115】。在這個模型中，後代高血壓與Ang II依賴性高血壓有關，伴隨成年後代的腎ACE活性增加以及AGT和ACE mRNA表達上升【83】。母體缺氧是另一種導致後代CKM的模型，與對Ang II的血壓反應編程有關【116,117】。

各種藥物和化學物質的暴露可以誘導後代的CKM表型，這是由RAS介導的。產前接觸地塞米松會上調RAS組分，並導致成年大鼠後代出現肥胖、高血壓、胰島素抵抗和腎臟疾病【92,118,119,120,121】。產前接觸糖皮質激素會導致後代高血壓，並伴隨雷尼、PRR、ACE和AT1R表達的上調【92,118】。另一項研究顯示，產前接觸地塞米松導致β細胞功能障礙和由於ACE2表達抑制引起的葡萄糖不耐受【119】。

此外，產前接觸尼古丁會導致高血壓、高脂血症、脂肪肝和腎臟疾病，所有這些都是成年後代CKM相關的特徵【122,123,124,125】。報導指出，因為產前接觸尼古丁，雄性大鼠後代對Ang II的高血壓效應敏感。另外一個例子是乙醇暴露。產前接觸乙醇可以誘導成年大鼠後代的腎臟疾病，並伴隨RAS的異常【126】。產前接觸乙醇時，ACE和AT1R的基因表達增加，而AT2R、ACE2和MAS的表達則減少【126】。

此外，表1顯示，產前接觸2,3,7,8-四氯二苯二噁英（TCDD）或二（2-乙基己基）鄰苯二甲酸酯（DEHP）會誘導成年大鼠後代的CKM表型【128,129,130,131,132,133】。在母體接觸TCDD的模型中，後代高血壓與腎臟AT1R表達增加有關【128】。在母體接觸DEHP的模型中，腎臟發育受損和成年腎臟疾病歸因於RAS的抑制【130】。

總之，各種母體損害在動物模型中被用來研究RAS的編程及其對後代心血管、腎臟和代謝健康的後續影響。這些研究強調了可修改RAS的各種機制，並強調了針對RAS進行重新編程干預的必要性，這是早期預防CKM綜合徵的關鍵步驟。

6. 針對RAS的重新編程策略

迄今為止，旨在減輕與DOHaD相關機制的早期生命干預策略範圍廣泛，包括避免風險因素、實施營養干預、使用藥物療法以及生活方式的改變【138,139,140】。考慮到近年來我們對後代RAS編程機制的理解取得了重大進展，有必要制定創新的重新編程策略，以針對RAS預防CKM綜合徵。目前，用於治療高血壓、心血管疾病（CVD）和慢性腎病（CKD）的藥物包括ACE抑制劑（ACEIs）和血管緊張素II受體拮抗劑（ARBs）。它們的使用與高風險患者的生存率改善以及顯著的心血管和腎臟益處相關【18】。然而，關於這些藥物對CKM綜合徵的重新編程效果的信息仍然有限。表2匯總了文獻，詳細說明了針對CKM表型的RAS靶向干預的使用，特別集中於在臨床表型出現之前啟動的干預措施。

目前，已經在CKM綜合徵的動物模型中檢驗了幾種針對RAS的干預措施，包括腎素抑制劑【101,141,142,143】、ACE抑制劑（ACEIs）【143,144,145,146,147,148】、ARBs【141,149,150,151】、AT1R反義核酸【152】以及ACE2活化劑【153】。多種針對RAS的干預措施在抵抗CKM特徵方面的主要保護效果，主要集中在高血壓，其次是腎病【148,151,153】和心血管疾病（CVD）【143,151】。雖然抑制RAS在解決CKM綜合徵的其他方面（如肥胖、肝脂肪變性和糖尿病）中顯示出優勢【21,22,23,24】，但其對這些表型重新編程的影響仍不明確。

關於RAS基礎治療的重新編程效果的研究，主要在10至30周齡的老鼠中進行，這大致對應於人類的兒童到青少年階段【154】。然而，大多數這些研究主要集中於雄性個體，並未探討不同劑量水平的影響。進一步的研究是必要的，以澄清這些觀察到的效果是否以劑量或性別為依賴。

早期抑制經典RAS軸的提議旨在重新編程異常活化的RAS，從而預防CKM綜合徵。在小鼠中，腎臟發展在出生後的1-2周內完全完成，心肌細胞在出生後第9天後很少重新進入或通過細胞週期。因此，適當的治療窗口包括在幼年後代中啟動治療，最早在大多數小鼠模型中出生後的2周開始。如表2所列，典型的治療期涉及在2至4周齡時對幼年後代進行aliskiren【101,142】、captopril【144】或losartan【149,150】的治療。這旨在減輕不良的編程過程，同時不損害腎臟發展。

目前，aliskiren是首個獲批用於治療高血壓的腎素抑制劑。兩項研究表明，當在2-4周齡的後代中給予aliskiren時，可以預防那些母親進食高果糖飲食【101】或受到熱量限制【142】的成年人高血壓。另一項研究則探討了在出生後第12至18天期間給予aliskiren和lisinopril以阻止高血壓和糖尿病視網膜病變在糖尿病（mRen-2）27大鼠模型中的潛力【143】。aliskiren顯示出比lisinopril更優越的視網膜保護，儘管lisinopril在正常化血壓方面表現得更好【143】。然而，aliskiren未能阻止PRR與其配體之間的相互作用。儘管有報導顯示，PRR抑制肽（如手柄區域肽和PRO20）在動物模型中表現出積極效果【155,156】，但對其特異性和有效性仍存在疑問【157】。人們對於未來開發針對PRR的特異性非肽抑制劑能在（前）腎素–PRR抑制方面取得良好結果持有樂觀態度。

自發性高血壓大鼠（SHR）作為主要的必需性高血壓和相關代謝紊亂的動物模型被使用【158】。在斷奶後的早期給予ACE抑制劑（如captopril【145】或perindopril【148】）為期3周已顯示出在成年SHR中預防高血壓的效果。同樣，早期使用captopril【144】或enalapril【146】對於由母親蛋白質限制所編程的後代高血壓也展現出有益的效果。

Losartan作為在編程的CKM綜合徵中唯一的ARB進行了研究（見表2）。在子宮胎盤功能不全的大鼠模型中，於5至8周齡期間給予losartan已被發現可以保護成年後代免受高血壓、血管功能障礙和腎病的影響【151】。另一項研究強調了早期使用AT1R反義核酸對抗SHR高血壓的預防潛力【152】。值得注意的是，AT1R反義核酸的施用在出生後第5天進行【152】，其對腎單位數量的影響尚未探討。

藥物干預傳統上專注於抑制經典RAS。然而，隨著替代RAS的識別，研究人員已探討激活這一非經典RAS的替代策略，直到最近才取得有限的成功【159】。令人驚訝的是，對於將這一方法應用於編程的CKM綜合徵的關注較少。表2中強調的結果表明，只有兩項研究記錄了在懷孕期間給予diminazene aceturate（DIZE）或ANG-(1-7），這些潛在的ACE2活化劑能減輕成年SHR後代的高血壓和腎纖維化【153】。

儘管激活非經典RAS軸在各種疾病中具有治療潛力，但仍需進一步研究以明確其對CKM編程的重新編程效果。文獻中存在一個重要的缺口，即對RAS的關鍵組件進行更深入的理解，以便採取針對性的方法，並確定預防CKM綜合徵的最佳治療窗口。

結論與未來方向

儘管RAS（腎素-血管緊張素系統）的失調被認為是促進CKM（心腎代謝）綜合徵組成部分編程的因素之一，但該領域仍然存在重大缺口，主要是由於方法論的限制以及缺乏共識，這妨礙了其臨床實踐的轉化。

一個主要未解決的問題是缺乏同時量化整個RAS組件表達和活性的綜合分析研究。在實驗環境中，鑑於RAS信號傳導的複雜性，僅依賴於孤立組件的分析可能會導致對系統功能狀態的誤解。

使用藥物來調節RAS在臨床實踐中已經得到廣泛認可，儘管在胎兒編程領域仍在逐步發展。本綜述展示了來自動物模型的數據，顯示各種基於RAS的療法在CKM編程中展現出正面影響，包括腎素抑制劑、ACE抑制劑（ACEIs）、ARBs、AT1R反義核酸和ACE2活化劑。然而，對於早期RAS干預措施的重新編程效果，無論是單獨還是聯合應用，仍然不完整且難以預測。因此，未來的努力應該集中於開發最佳方法，以便更全面地理解RAS，確保RAS基於療法的正確方向。此外，還必須關注確定性別依賴性的最佳劑量，以在不增加毒性的情況下最大化收益，為臨床轉化做準備。

儘管在各種基於RAS的藥物的可及性方面已取得實質性進展，但對其在CKM綜合徵每個組件的重新編程效果的深入探索仍然缺乏。另一個挑戰在於確定不同RAS基於療法的具體發展窗口，以重新編程驅動不同CKM表型的過程，這些仍待進一步澄清。儘管如此，本綜述通過建立RAS與CKM綜合徵發展起源之間的聯繫，標誌著進展。它提供了寶貴的見解，未來有望為潛在的基於RAS的干預措施鋪平道路，以減輕CKM綜合徵的全球負擔。

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