Friday, April 4, 2025
4/4/2025
Insulin and Immune Mechanisms in Obesity-Induced Renal Disease - Prepubertal childhood obesity (PPO) has emerged as an epidemic and major health problem in the United States. Recent studies suggest that PPO is associated with increased risk of renal injury in children. The consequences of PPO as an independent risk factor for renal disease in the absence of diabetes has received little attention. Recently, we observed our obese rat model (SSLepRmutant) develops insulin resistance (IR) and progressive proteinuria in the absence of diabetes during the prepubescent stage. In the current proposal, we will use the SSLepRmutant rat to explore several mechanisms that may contribute to the development of renal disease during PPO. Changes in tubular glucose and energy metabolism are now considered as major characteristics of renal disease. Under normal physiological conditions, fatty acid oxidation (FAO) is the main source of energy in renal proximal tubules (PTs), and insulin stimulates glucose transport and inhibits gluconeogenesis (glucose production) in the PT. However, IR is associated with increased glucose transport and decreased glucose output in cultured PT cells under hyperglycemic conditions, which could potentially lead to glucotoxicity, mitochondria dysfunction, and tubular injury. Moreover, clinical and animal studies have demonstrated that both gluconeogenesis and glycolysis (glucose breakdown) are elevated, while FAO is reduced during the later stages of diabetic renal disease. However, little is known about these pathways in the PT under IR, non-diabetic conditions in the early stages of renal injury. Our central hypothesis is that IR alters PT glucose transport and energy metabolism and promotes tubular injury. In Specific Aim 1, we propose to investigate whether IR in the PT triggers increased gluconeogenesis contributing to mitochondrial dysfunction early during non-diabetic PPO. In Specific Aim 2, our goal is to examine whether limiting PT glucose transport can improve energy metabolism and mitochondrial function of the PTs, thereby preventing renal hyperfiltration and reducing inflammation and progressive proteinuria during non-diabetic PPO. Furthermore, these aims also will employ state-of-the art mass spectrometry proteomics to identify molecular mechanisms in isolated PTs from both, SS and SSLepRmutant rats. Overall, results from these studies will identify molecular mechanisms that play a crucial role of IR in the early progression of renal disease during PPO which increases risk of CKD in adulthood.
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