Protective Arm of Renin‐Angiotensin System: Evidence of Nephroprotective Effects Against Acute Kidney Injury

ABSTRACT

Acute kidney injury (AKI) is a global health problem due to its high and increasing incidence, morbidity and mortality. 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‐angiotensin 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 (1–7) and its receptor Mas (MasR), and alamandine and its receptor, Mas‐related G protein–coupled 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‐based evidence that such modulation exerts beneficial effects in experimental models of ischemia–reperfusion, 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.