Raul R. Rodrigues-Diez

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes mellitus and a leading cause of end-stage kidney disease. Despite its rising incidence, awareness and early detection of renal complications remain limited. Current research in DKD aims to identify non-invasive biomarkers for early diagnosis and to develop effective therapies that go beyond controlling risk factors, as few options are available to halt or reverse kidney inflammation and fibrosis. MicroRNAs (miRNAs), key regulators of gene expression, have emerged as promising candidates for both diagnosis and treatment in DKD. Among them, miR-802 has gained attention due to its role in modulating inflammatory, fibrotic, and metabolic pathways. Elevated levels of miR-802 correlate with renal inflammation and fibrosis in diabetic and obese models, highlighting its potential as both a diagnostic biomarker and a therapeutic target. This review focuses on the emerging evidence supporting the involvement of miR-802 in the pathogenesis of DKD and its potential role as a diagnostic and therapeutic tool. In addition, considering that miR-802 has also been implicated in other diseases, such as cancer, where it may act either as a tumor suppressor or an oncogene, these contrasting effects will also be discussed as part of the broader context to better understand the multifaceted biological roles of miR-802. This review emphasizes the need for further research to clarify the molecular mechanisms of miR-802 and to assess its potential for clinical translation in DKD.

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.