Obesity and kidney disease: from population to basic science and the search for new therapeutic targets.
The global burden of kidney disease is increasing strikingly in parallel with increases in obesity and diabetes. Indeed, chronic kidney disease (CKD) and end-stage renal disease (ESRD) coupled with comorbidities such as obesity, diabetes, and hypertension cost the health care system hundreds of billions of dollars in the US alone. The progression to ESRD in patients with obesity and diabetes continues despite widespread use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) along with aggressive blood pressure and glycemic control in these high-risk populations. Thereby, it is increasingly important to better understand the underlying mechanisms involved in obesity-related CKD in order to develop new strategies that prevent or interrupt the progression of this costly disease. In this context, a key mechanism that drives development and progression of kidney disease in obesity is endothelial dysfunction and associated tubulointerstitial fibrosis. However, the precise interactive mechanisms in the development of aortic and kidney endothelial dysfunction and tubulointerstitial fibrosis remain unclear. Further, strategies specifically targeting kidney fibrosis have yielded inconclusive benefits in human studies. While clinical data support the benefits derived from inhibition of the RAAS, there is a tremendous amount of residual risk for the progression of kidney disease in individuals with obesity and diabetes. There is promising experimental data to suggest that exercise, targeting inflammation and oxidative stress, lowering uric acid, and targeting the mineralocorticoid receptor signaling and/or sodium channel inhibition could improve tubulointerstitial fibrosis and mitigate progression of kidney disease in persons with obesity and diabetes.
Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA; Diabetes and Cardiovascular Center, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Division of Nephrology and Hypertension, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Division of Endocrinology and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA. Electronic address: adam.whaley-connell@va.gov.
Adam
A
Whaley-Connell
Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA; Diabetes and Cardiovascular Center, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Division of Endocrinology and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA; Department of Medical Pharmacology and Physiology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA.
James R
JR
Sowers
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D006801:Humans; D007333:Insulin Resistance; D007668:Kidney / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000209:etiology*; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012079:Renal Circulation; D012084:Renin-Angiotensin System
D018161:Receptors, Mineralocorticoid; D000450:Aldosterone
chronic kidney disease; mineralocorticoid receptor; obesity; tubulointerstitial fibrosis