Letter to the Editor in response to the article “Dysregulation of miR ‐21‐5p in diabetic nephropathy and its role in inflammatory response”

Dear Editor, We read with interest the article by Zhang et al. entitled “Dysregulation of miR-21-5p in diabetic nephropathy and its role in inflammatory response” published in Journal of Diabetes Investigation1. The study presents important clinical and cellular evidence that serum miR-21-5p is upregulated in diabetic nephropathy (DN) and may serve as a diagnostic marker. While the findings are valuable, several aspects could be further explored to strengthen their translational relevance. First, elucidating the direct molecular targets of miR-21-5p in renal cells is essential for mechanistic understanding. Although the authors show that miR-21-5p knockdown reduces inflammation and proliferation, the specific downstream targets in kidney cells remain unidentified. While PDCD4 and PFKFB2 are mentioned in other contexts, direct validation in renal cells—for example, via luciferase reporter assays and Western blot—would clarify its pathogenic role. Such an approach is well established in miRNA research; for instance, studies have demonstrated that miRNAs such as miR-192-5p can directly target specific genes (e.g., GLP-1R) to regulate fibrosis in DN2. Similar direct target validation for miR-21-5p would transform correlation into causation and support therapeutic development. Second, the robustness of clinical associations could be enhanced by multivariate analysis. The correlations between miR-21-5p and eGFR or inflammatory markers are compelling but derived from univariate tests. Renal function is influenced by factors such as age, hypertension, and diabetes duration. Multivariable regression would help determine whether miR-21-5p is an independent predictor of DN severity, as emphasized in contemporary biomarker guidelines3. Third, diagnostic specificity should be tested against nondiabetic kidney diseases. The study successfully distinguishes DN from T2DM without nephropathy and healthy controls. To establish specificity for diabetic kidney disease, however, comparison with other chronic kidney diseases—such as hypertensive nephropathy or IgA nephropathy—is needed, as emphasized in recent biomarker discovery studies4. Notably, miR-21-5p has been reported to be elevated in conditions like IgA nephropathy, underscoring the necessity of such comparative validation4. Including such controls would clarify whether miR-21-5p is a general marker of renal injury or specific to the diabetic milieu. In summary, Zhang et al. have highlighted miR-21-5p as a promising candidate in DN. Further work to identify its renal targets, perform adjusted clinical analyses, and include disease-specific controls will be key to translating these observations into clinically useful tools. None. The author declares no conflict of interest. Approval of the research protocol: None. Informed consent: None. Registry and the registration no. of the study/trial: None. Animal studies: None. The data that support the findings of this study are available in Pubmed at https://pubmed.ncbi.nlm.nih.gov/40839492/, reference number https://doi.org/10.1111/jdi.70098. These data were derived from the following resources available in the public domain: J Diabetes Investig. 2025 Nov;16(11):2033–2039. https://doi.org/10.1111/jdi.70098.