Hyperuricemia-induced renal fibrosis: Mechanisms and advances in pharmacological studies using uricase-deficient animal models.

Abstract

The high incidence of hyperuricemia (HUA) is largely attributed to imbalances between uric acid production, distribution, and excretion. HUA can lead to renal fibrosis, which in turn causes a progressive decline in kidney function and the development of serious conditions such as chronic kidney disease (CKD). Therefore, the effective prevention and treatment of HUA-induced renal fibrosis is of critical importance. Elevated serum uric acid acts as a key trigger for HUA-induced renal fibrosis, while uric acid accumulation in kidney tissues, especially in the medulla, may play an even essential role in this process. However, few studies have focused on the role of tissue uric acid, even though increased tissue uric acid can activate macrophages and mediate chronic inflammation as well as other mechanisms that initiate or worsen renal fibrosis. Moreover, current clinical drug interventions yield unsatisfactory outcomes and are often associated with numerous adverse effects, emphasizing the urgent need for new therapeutic agents. In recent years, the use of clinically relevant uricase-deficient animal models in pharmacological studies has increased, potentially representing the forefront of research in HUA-induced renal fibrosis. However, a comprehensive review of these studies is still needing. This review explains how uric acid affects the kidney and induces renal fibrosis, summarizes the underlying mechanisms to inform clinical diagnosis, treatment, and drug development, and consolidates the current status of clinical therapies and pharmacological research using uricase-deficient animal models, with the aim of identifying promising agents for the effective prevention and treatment of HUA-induced renal fibrosis.