NEK10 Drives Lipid Disturbances that Induce G2/M Phase Arrest in Renal Tubular Cells Under Albumin Overload.

Abstract

Albuminuria is a recognized independent risk factor for renal interstitial fibrosis and may induce G2/M phase arrest in proximal tubular epithelial cells (PTECs). 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 (TIF). Human renal tubular cells (HK-2) exposed to 10 mg/mL bovine serum albumin (BSA) for 24 - 48 hours exhibited 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. In vivo, NEK10 knockdown via recombinant adenovirus (rAAV-shNEK10) in unilateral ureteral obstruction (UUO) mice attenuated BSA-induced renal fibrosis, lipid accumulation, and tubular injury. Clinically, immunohistochemical analysis of kidney biopsies from chronic kidney disease (CKD) patients revealed elevated NEK10 expression, correlating with urinary protein levels (>3.5 g/24 h) and interstitial fibrosis. 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.