bioRxiv. 2026 Feb 27. pii: 2026.02.20.707069. [Epub ahead of print]
Metabolic dysfunction-associated kidney disease (MDAKD) is closely linked to dietary excess, but models that capture early kidney injury without obesity are limited. We fed male C57BL/6J (6J) and C57BL/6N (6N) mice a high-fat, high-sodium (HF/HNa) or control diet for 16 weeks. HF/HNa feeding did not alter body weight, adiposity, or total food intake; however, it increased dietary energy and sodium exposure, kidney mass, water intake, and urine volume. GFR declined modestly in 6J mice, whereas 6N mice maintained or slightly increased GFR. Both substrains showed increased urinary albumin, creatinine, KIM-1, and NGAL, while cystatin C rose predominantly in 6N mice, indicating strain-dependent tubular injury. Whole-kidney trichrome staining revealed increased fibrotic area with HF/HNa, particularly in 6N mice, without significant changes in glomerular morphology. In isolated renal mitochondria, oxygen consumption was preserved, but ATP production and ATP:O ratios were reduced, with unchanged citrate synthase activity and OXPHOS protein abundance, consistent with early mitochondrial bioenergetic uncoupling. Exploratory urinary proteomics in 6J mice identified HF/HNa-associated changes in proteins linked to tubular stress and extracellular matrix remodeling. These findings define an early MDAKD-like renal phenotype with strain-specific functional responses, tubular injury, fibrosis, and impaired mitochondrial ATP efficiency.
Translational Statement: Metabolic Dysfunction-Associated Kidney Disease (MDAKD) is a leading driver of chronic kidney disease (CKD) in the world. In addition to obesity and related comorbidities, renal mitochondrial dysfunction is thought to be a key contributor to the development of CKD in patients with MDAKD; however, few models recapitulate the progression of MDAKD. We couple well-established mouse models of obesity, namely the C57Bl/6J and C57Bl/6N mouse lines, with a high-fat, high-salt diet to induce renal mitochondrial dysfunction, leading to early stages of MDAKD as indicated by widespread fibrosis and mild reduction in glomerular filtration rate, though these effects were strain-dependent. We identify diet-induced mitochondrial dysfunction as a common feature in both mouse strains, suggesting impairments in mitochondrial respiration and oxidative ATP production are indeed a contributing factor to the development of MDAKD. This study highlights the role of energetic impairments in the pathogenesis of MDAKD and may guide future therapies for CKD.