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Despite progress in understanding its pathophysiology, there are currently no pharmacological therapies that improve survival, limit damage, or accelerate recovery, except for supportive interventions and renal replacement therapies. Cumulative knowledge indicates that during AKI, the dynamic balance between the two arms of renin\u2010angiotensin system (RAS) is disturbed, activating the classical and reducing the protective arm. This imbalance determines pathophysiological outcomes, so the modulation of protective arm emerges as a key therapeutic strategy. This arm offers several pharmacological targets such as angiotensin II type 2 receptor (AT2R), angiotensin converting enzyme 2 (ACE2), angiotensin (1\u20137) and its receptor Mas (MasR), and alamandine and its receptor, Mas\u2010related G protein\u2013coupled receptor D (MrgD). This review presents current evidence on the modulation of the protective arm of the RAS, its role in AKI pathophysiology, and its potential as a therapeutic target, presenting literature\u2010based evidence that such modulation exerts beneficial effects in experimental models of ischemia\u2013reperfusion, septic and nephrotoxic AKI. This evidence emphasizes the potential of these targets for drug development in the context of AKI. Further investigation of this RAS axis may expand our understanding of AKI pathophysiology and open new avenues for the development of targeted, effective, and safer therapeutic strategies.<\/jats:p>","DOI":"10.1111\/apha.70292","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T03:42:39Z","timestamp":1786506159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protective Arm of Renin\u2010Angiotensin System: Evidence of Nephroprotective Effects Against Acute Kidney Injury"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6007-5861","authenticated-orcid":false,"given":"Mar\u00eda Fernanda","family":"Fussi","sequence":"first","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (IFISE\u2010CONICET)  Rosario Argentina"},{"name":"\u00c1rea Farmacolog\u00eda, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas Universidad Nacional de Rosario  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2019-1249","authenticated-orcid":false,"given":"Sara Mar\u00eda","family":"Molinas","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (IFISE\u2010CONICET)  Rosario Argentina"},{"name":"\u00c1rea Farmacolog\u00eda, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas Universidad Nacional de Rosario  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32563-2"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000882"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60126-X"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00284-z"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.2"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.11200919"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.12.018"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9800838"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.120.000281"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.123.21364"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.5.e1"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1432869100"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301077"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45161"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006010017"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00818.x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2011.16"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2014.180"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2018.10.007"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000142934"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002312"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00184.2024"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2144"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000476078"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2018.03.028"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2000.278.1.F1"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00099.2020"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.34067\/KID.0000000000000321"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-025-02229-5"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016070734"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389203043379693"},{"issue":"7","key":"e_1_2_11_33_1","first-page":"S13","article-title":"Renin\u2010Angiotensin System: A Dual Tissue and Hormonal System for Cardiovascular Control","volume":"10","author":"Johnston C. 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