The Role of Mitochondrial AKT1 Signaling in Renal Tubular Injury of Metabolic Syndrome

Metabolic syndrome (MetS) is increasingly recognized as a contributor to kidney disease, yet the underlying mechanisms remain poorly defined. Recent studies suggest a pivotal role for mitochondrial dysfunction in renal injury. We hypothesized that mitochondrial AKT1 signaling in renal tubules plays a critical role in MetS-related kidney injuries.

MetS was induced in a 8-week-old C57BL/6 male mice using a high-fat diet (HFD) for 4 months compared with controls on a standard chow diet. Additional experiments were conducted in DB/DB diabetic mice and their controls (WT and DB/WT) to validate findings. Renal metabolic parameters, mitochondrial AKT1 signaling, and markers of kidney injury were assessed.

MetS mice exhibited significant weight gain, altered glucose handling, and decreased energy expenditure. Although kidney size and basic renal function (blood urea nitrogen [BUN], creatinine) were unchanged, markers of renal damage, including proteinuria (P = 0.0002) and KIM-1 (P < 0.0001) were elevated. Histological analyses showed increased tubular injury (P < 0.0001) and glomerulosclerosis (P = 0.0004). Transmission electron microscopy revealed aberrant mitochondria (P < 0.001), with reduced cristae length (P = 0.012) and numbers (P < 0.001). Immunohistochemistry, immunofluorescence, and Western blot analysis confirmed increased phosphorylated AKT1 (pAKT1) in the mitochondria of renal tubules (P = 0.0474), findings corroborated in DB/DB mice. This translocation of pAKT1 into mitochondria correlated with decreased cell viability upon inhibition of heat shock protein 90, indicating a dependency on mitochondrial AKT1 for cell survival.

These findings underscore the mechanistic link between mitochondrial AKT1 signaling and renal tubular injury in MetS. Targeting mitochondrial dysfunction may offer new avenues for preventing and treating kidney diseases in patients with MetS.