American journal of nephrology · 2025
NEK10 Drives Lipid Disturbances That Induce G2/M Phase Arrest in Renal Tubular Cells under Albumin Overload.
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Wang Pingan, Liu Ting, Liu Minna, Dang Yangjie, Zhang Junming, Gan Yukun, Zhu Mengxue, Zhang Yue, Wei Qi, Liu Limin
Аннотация
INTRODUCTION: Albuminuria is an independent risk factor for renal interstitial fibrosis and induces G2/M phase arrest in proximal tubular epithelial cells. Although protein overload disrupts fatty acid metabolism, the mechanistic link to cell cycle arrest remains unclear. This study investigates the role of NIMA-related kinase 10 (NEK10), a serine/threonine kinase implicated in cell cycle regulation, in mediating albumin-induced lipid dysregulation and G2/M arrest, which exacerbate tubulointerstitial fibrosis.
METHODS: Human renal tubular cells (HK-2) were exposed to 10 mg/mL bovine serum albumin (BSA) for 24-48 h. In vivo, NEK10 was knocked down using recombinant adenovirus (rAAV-shNEK10) in unilateral ureteral obstruction (UUO) mice treated with BSA. Clinically, NEK10 expression was assessed via immunohistochemistry in kidney biopsies from chronic kidney disease (CKD) patients with varying urinary protein levels.
RESULTS: BSA-exposed HK-2 cells showed lipid droplet accumulation, reduced ATP levels, impaired fatty acid oxidation, and increased G2/M phase arrest. These effects coincided with upregulated NEK10 expression and ERK1/2 phosphorylation. NEK10 knockdown in UUO mice attenuated BSA-induced renal fibrosis, lipid accumulation, and tubular injury. In CKD patients, elevated NEK10 expression correlated with higher urinary protein levels (>3.5 g/24 h) and interstitial fibrosis.
CONCLUSION: Our findings identify NEK10 as a critical regulator of albumin-induced metabolic dysfunction and cell cycle arrest, suggesting therapeutic targeting of NEK10 may mitigate fibrosis in proteinuric kidney diseases.
METHODS: Human renal tubular cells (HK-2) were exposed to 10 mg/mL bovine serum albumin (BSA) for 24-48 h. In vivo, NEK10 was knocked down using recombinant adenovirus (rAAV-shNEK10) in unilateral ureteral obstruction (UUO) mice treated with BSA. Clinically, NEK10 expression was assessed via immunohistochemistry in kidney biopsies from chronic kidney disease (CKD) patients with varying urinary protein levels.
RESULTS: BSA-exposed HK-2 cells showed lipid droplet accumulation, reduced ATP levels, impaired fatty acid oxidation, and increased G2/M phase arrest. These effects coincided with upregulated NEK10 expression and ERK1/2 phosphorylation. NEK10 knockdown in UUO mice attenuated BSA-induced renal fibrosis, lipid accumulation, and tubular injury. In CKD patients, elevated NEK10 expression correlated with higher urinary protein levels (>3.5 g/24 h) and interstitial fibrosis.
CONCLUSION: Our findings identify NEK10 as a critical regulator of albumin-induced metabolic dysfunction and cell cycle arrest, suggesting therapeutic targeting of NEK10 may mitigate fibrosis in proteinuric kidney diseases.