Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease.

Background/Objectives: Chronic kidney disease (CKD) is twice as prevalent in individuals with obesity-associated non-alcoholic fatty liver disease (Ob-NAFLD), highlighting the need to determine the link and mechanisms of kidney injury as well as explore therapies. Metformin, a first-line treatment for type 2 diabetes, shows promise in managing NAFLD, but its renal benefits in Ob-NAFLD remain unclear. This study investigates the impact of Ob-NAFLD on kidney injury and assesses the potential protective effects of metformin. Methods: Five-week-old female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for 8 weeks to induce Ob-NAFLD, then fed the diet with Metformin for 10 weeks. Kidneys were collected for histopathological and biochemical analyses. Results: Histopathological studies showed increased tubular injury, mesangial matrix expansion, and fibrosis in kidneys with Ob-NAFLD compared to lean control (LC) rats. Immunohistochemistry further revealed an elevated macrophage and neutrophil infiltration and increased levels of nitrotyrosine and p22phox in Ob-NAFLD kidneys. Furthermore, Ob-NAFLD rat kidneys showed upregulation of TNF-α and CCL2 genes and increased levels of caspase-3 (total and cleaved). Interestingly, metformin treatment significantly decreased TNF-α mRNA and blunted nitrotyrosine levels, and modestly reduced immune cell infiltration in Ob-NAFLD. Conclusions: These findings indicate that Ob-NAFLD promotes CKD as evidenced by tubular injury, oxidative stress, inflammation, and fibrosis. While short-term metformin treatment showed anti-oxidative and anti-inflammatory effects in Ob-NAFLD, its impact on structural kidney damage was limited, highlighting the need for longer treatment or alternative therapeutics such as oxidant scavengers and anti-inflammatory drugs to effectively mitigate renal pathologies.

Ischemia–reperfusion injury (IRI) is a major driver of acute kidney injury and development of chronic kidney disease. Although complement activation worsens IRI, the roles of upstream (C3) versus downstream (C5) components remain unclear. Renal IRI was surgically induced in C3 knockout (C3 ⁻ / ⁻ ) and C5 knockout (C5 ⁻ / ⁻ ) Lewis rats, and the renal function as well as histopathology were systematically assessed. Further, quantitative proteomics coupled with pathway enrichment analysis was performed to define complement‐dependent mechanisms. C3 and C5 deficiency conferred strong protection against renal IRI with improved renal function, reduced tubular necrosis, and lower expression of injury markers (KIM‐1, NGAL). Post‐IRI, C3 ^−/− enhanced mitochondrial, metabolic, and purine pathways while suppressing immune and extra‐cellular matrix programs. C5 ^−/− affected extracellular matrix remodeling and structural pathways with modest immune suppression. We demonstrate for the first time that upstream C3 ^−/− impacts a diverse range of renal injury and repair mechanisms compared to C5 ^−/− alone, although both interventions successfully reduced IRI‐mediated injury. Together, these findings highlight strategies for future complement‐based therapies targeting the upstream or downstream cascade.

Our study using a rat renal transplant model shows that cold storage (CS)-induced injury involves dysregulation of heat shock proteins in the kidney and provides proof of concept that targeting a single disrupted protein, heat shock protein 72 (Hsp72), can improve graft function.

Animal studies suggest that chronic monosodium glutamate (MSG) intake induces kidney damage by oxidative stress. However, the underlying mechanisms are still unclear, despite the growing evidence and consensus that α-ketoglutarate dehydrogenase, glutamate receptors and cystine-glutamate antiporter play an important role in up-regulation of oxidative stress in MSG-induced renal toxicity. This review summaries evidence from studies into MSG-induced renal oxidative damage, possible mechanisms and their importance from a toxicological viewpoint.

The peritoneal injection of monosodium glutamate (MSG) can induce kidney injury in adult rats but the effects of long-term oral intake have not been determined. We investigated the kidney histology and function in adult male Wistar rats that were fed ad libitum with a standard rat chow pellet and water with or without the addition of 2 mg/g body weight MSG/day in drinking water (n=10 per group). Both MSG-treated and control animals were sacrificed after 9 months when renal function parameters, blood and urine electrolytes, and tissue histopathology were determined. MSG-treated rats were more prone to kidney stone formation, as represented by the alkaline urine and significantly higher activity product of calcium phosphate. Accordingly, 3/10 MSG-treated rats developed kidney stones over 9 months versus none of the control animals. Further, 2/10 MSG-treated rats but none (0/10) of the controls manifested hydronephrosis. MSG-treated rats had significantly higher levels of serum creatinine and potassium including urine output volume, urinary excretion sodium and citrate compared to controls. In contrast, MSG-treated rats had significantly lower ammonium and magnesium urinary excretion. Oral MSG consumption appears to cause alkaline urine and may increase the risks of kidney stones with hydronephrosis in rats. Similar effects in humans must be verified by dedicated studies.