Altered expression of AMPK ULK1 PINK1 Parkin mitophagy-related genes and clinicopathological correlates in renal tissue from patients with diabetic nephropathy

Abstract Mitophagy impairment is increasingly recognized as a driver of diabetic nephropathy (DN) in preclinical models, with limited validation in human tissue samples. This study aimed to evaluate the expression profile of mitophagy-related gene panel in human renal cortical biopsies and its clinicopathological correlation in advanced DN. A total of 66 kidney tissue and blood samples were collected from DN patients (n = 33) and controls (n = 33), with control tissue obtained from normal regions of nephrectomy specimens. mRNA expression of mitophagy-related genes in kidney tissue was measured using qRT-PCR and correlated with clinical, metabolic, renal, and histopathological parameters. Receiver operating curve (ROC) analysis was performed to assess discriminatory performance of transcripts. To further contextualize findings, in-silico protein–protein interaction mapping, pathway enrichment, and disease-gene association analyses were conducted. DN patients exhibited significantly elevated fasting glucose, insulin, HbA1c, lipid parameters, and HOMA-IR, alongside lower QUICKI (all p < 0.001) compared to controls. mRNA expression of PRKAA1 , ULK1, PINK1 , MAP1LC3B , and BECN1 was significantly reduced ( p < 0.05), while no significant differences were observed for PRKN , SQSTM1 , and MTOR. Gene expression showed significant correlations with renal function parameters (eGFR, creatinine) and various metabolic parameters, but no significant correlation with histopathological severity. ROC analysis demonstrated higher exploratory discriminatory performance for PINK1 (AUC = 0.762) and ULK1 (AUC = 0.748). In-silico analyses revealed enrichment of target genes in mitophagy-related pathways relevant to DN ( p < 0.001, 87.5% intersection). Our findings demonstrate reduced expression of key genes of AMPK/ULK1/PINK1/Parkin mitophagy-axis in human DN renal tissue, with significant association with renal dysfunction and metabolic impairment. PINK1 and ULK1 showed comparatively higher exploratory discriminatory performance, supporting their potential relevance in DN pathophysiology. Further studies in larger and clinically diverse DN cohorts are required to validate these findings and explore their clinical implications.