Dual roles of renal tubular mitochondrial Akt1 in protecting against diabetic nephropathy and improving body glucose metabolism
Year: 2026
Type: article
Abstract: Diabetic nephropathy (DN) is a leading cause of chronic kidney failure. We hypothesized that mitochondrial Akt1 dysfunction in renal proximal tubules plays a pathogenic role in DN development and that its activation may reverse DN progression. To study this signaling pathway, we generated a transgenic mouse model harboring a renal tubule-specific, tamoxifen-inducible, mitochondria-targeted constitutively active Akt1 (KMCAKT). Type 2 diabetes was induced by a high-fat, high-fructose diet (HFFD) for 40 weeks. Renal histology and function were evaluated, and glucose metabolism was assessed using dynamic glucose testing. We found that HFFD feeding resulted in the development of DN in control non-induced KMCAKT mice, whereas KMCAKT mice with constitutively active mitochondrial Akt1, induced by tamoxifen injection (TAM), exhibited a significant improvement in kidney dysfunction and histology. Urinary albumin, fasting plasma BUN levels, fibrosis, and Jablonski scores were all markedly improved in HFFD-TAM-KMCAKT mice compared with controls, while levels of α-smooth muscle actin (αSMA) and transforming growth factor-β1 (TGFβ1) were significantly reduced. HFFD-TAM-KMCAKT mice exhibited lower fasting blood glucose and improved oral glucose tolerance, while basal and stimulated insulin levels were higher, along with increased beta cell mass and insulin secretion (HOMA-β) compared with controls. Hyperglycemic clamp studies confirmed increased insulin secretion in HFFD-TAM-KMCAKT mice. We conclude that tubular mitochondrial Akt1 plays a key role in DN progression. Restoring tubular mitochondrial Akt1 signaling may represent a novel approach to reverse the development of chronic kidney disease. We also identified previously unrecognized metabolic cross talk between renal tubular mitochondrial Akt1 and pancreatic insulin secretion that may modulate systemic glucose homeostasis.
Source: Journal of Endocrinology
DOI: 10.1530/joe-26-0143
Institutions: City Of Hope National Medical Center, City of Hope
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7204211514