Renin-angiotensin-system and clear cell renal carcinoma: research advances and future perspectives

Hypertension is a known risk factor for clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms remain elusive. Studies have confirmed that the renin-angiotensin system (RAS) plays a role beyond regulating blood pressure, influencing various aspects of tumor development and metastasis. Generally, activation of the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis elevates blood pressure and promotes tumor progression, while the activation of the angiotensin-converting enzyme 2 (ACE2)/[Ang-(1-7)]/Mas receptor (MasR) axis antagonizes these effects. Consequently, many cardiovascular drugs targeting the RAS may possess both hypotensive and antitumor properties. However, the role of RAS in ccRCC is controversial. To explore this, we reviewed the relevant literature. Surprisingly, apart from ACE2, the activation of RAS may facilitate the progression and metastasis of ccRCC. This unexpected finding suggests caution when using RAS inhibitors in ccRCC patients. This review provides an overview of the RAS, highlights research advances in RAS for ccRCC, elucidates the current status of RAS-targeted drugs in the treatment of ccRCC, and discusses the current challenges and future research directions in this field. In conclusion, the upregulation of other effector peptides and the activation of receptors in the RAS, apart from ACE2, may expedite ccRCC progression. Therefore, careful consideration is needed when using relevant drugs in ccRCC patients with hypertension. This synthesis of available evidence is crucial for informing the clinical management of ccRCC and guiding the development of novel therapeutic strategies.