The Role of Renin-Angiotensin System in Diabetic Nephropathy: An Update

Background and Aims: Diabetic nephropathy (DN) is an important complication of diabetes, leading to end-stage renal disease (ESRD) worldwide. This review aimed to explore the role of the renin-angiotensin system (RAS) in DN, highlighting current treatments and emerging therapeutic perspectives. Methods: We conducted a narrative review of the literature up to March 2024, focusing on the classical and alternative RAS axes, their implications in DN, and novel therapeutic approaches. Data were sourced from Scopus, PubMed, Scielo, and Cochrane databases. Results: The classical RAS axis, involving angiotensin-converting enzyme (ACE), Angiotensin II (Ang II), and the AT1 receptor, promotes vasoconstriction, sodium retention, and fibrosis in DN. Hyperglycemia-induced Ang II increases oxidative stress, contributing to glomerular hyperfiltration and kidney damage. Current treatments include ACE inhibitors and angiotensin receptor blockers (ARBs), which reduce blood pressure and proteinuria, delaying DN progression. In contrast, the alternative RAS axis, featuring ACE2, Ang-(1-7), and the Mas receptor, offers renoprotective effects by counteracting Ang II actions. Ang-(1-7) reduces inflammation, fibrosis, and podocyte apoptosis. ACE2 activators, Ang-(1-7), and Mas receptor agonists show promise in preclinical studies, reducing glomerular fibrosis and improving renal function. Ang-(1-9) and alamandine may also hold potential in future treatments. Emerging therapies, such as the SGLT2 inhibitors, also demonstrate benefits in reducing DN progression. Conclusion: While ACE inhibitors, ARBs, and SGLT2 inhibitors remain central to DN management, the ACE2-Ang-(1-7)-Mas axis presents a promising therapeutic target. Future research should focus on translating preclinical findings into clinical applications, potentially improving DN treatment.