Connecting glycation and lipotoxicity to mitochondrial dysfunction in diabetic kidney disease: A 'tubulocentric'...

Diabetic kidney disease (DKD) develops in 40% of diabetic patients, and it is one of the leading causes of end-stage kidney disease. The pathogenesis of DKD is multifaceted and, conventionally, is dominated by glomerular lesions that worsen at different stages of DKD, leading to proteinuria and declining kidney function. However, a significant proportion of diabetics do not develop proteinuria and instead show marked tubular injury. Hence, this shifts the research paradigm from 'glomerulo-' to a 'tubulocentric' view as a primary event with emerging diabetic tubulopathy. Moreover, proximal tubule epithelial cells have a central role in reabsorption and continuously require high energy, which is supplied by fatty acid oxidation in mitochondria. Indeed, elevated levels of advanced glycation end products (AGEs) in circulation during hyperglycemia induce lipotoxicity via Sterol regulatory element binding protein (SREBP). Excess lipid synthesis and accumulation exceed mitochondrial capacity for fatty acid oxidation, depriving the mitochondria of energy. However, the systematic association between AGEs, lipotoxicity and mitochondrial dysfunction remains elusive. Hence, the present review emphasizes diabetic tubulopathy in terms of glycation, lipid metabolism, and mitochondrial dysfunction, considering its clinical significance and its association with the development of a novel pharmacological approach for early detection of DKD.