Obesity, oxidative stress, and fibrosis in chronic kidney disease.
Obesity in combination with diabetes and hypertension likely is contributing to the increasing incidence of chronic kidney disease (CKD) in the 21st century worldwide and requires novel insights and strategies for treatment. There is an increasing recognition that the kidney has an important role in the complex inter-organ communication that occurs with the development of inflammation and fibrosis with obesity. Inhibition of the adiponectin-AMPK pathway has now become established as a critical pathway regulating both inflammation and pro-fibrotic pathways for both obesity-related kidney disease and diabetic kidney disease. AMPK regulates NFκB activation and is a potent regulator of NADPH oxidases. Nox4 in particular has emerged as a key contribtor to the early inflammation of diabetic kidney disease. AMPK also regulates several transcription factors that contribute to stimulation of the transforming growth factor-beta (TGF-β) system. Another key aspect of AMPK regulation is its control of mammalian target of rapamycin (mTOR) and mitochondrial biogenesis. Inhibition of PGC-1α, the transcriptional co-activator of mitochondrial biogenesis is being recognized as a key pathway that is inhibited in diabetic kidney disease and may be linked to inhibition of mitochondrial function. Translation of this concept is emerging via the field of urine metabolomics, as several metabolites linked to mitochondria are consistently downregulated in human diabetic kidney disease. Further studies to explore the role of AMPK and related energy-sensing pathways will likely lead to a more comprehensive understanding of why the kidney is affected early on and in a progressive manner with obesity and diabetes.
Center for Renal Translational Medicine, Institute for Metabolomic Medicine, Department of Medicine, University of California San Diego/Veterans Affairs San Diego Healthcare System , La Jolla, California, USA.
Kumar
K
Sharma
AMPK; NADPH oxidase; USF1; adiponectin; inflammation