Abstract
Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process.
Highlights
The exact mechanisms by which chronic inflammation contributes to chronic kidney disease (CKD) remain to be elucidated
All high fat diet (HFD) mice showed a marked increase in kidney weight and adipose tissue mass for gonadal, perirenal and mesenteric depots analyzed at all time points as compared to low fat diet (LFD) mice (Fig. 1B,C)
In C57BL/6J mice fed a LFD or a HFD, we investigated when and how renal pathology manifests at the functional and systemic level and how this associates with obesity and age-dependent inflammation
Summary
The exact mechanisms by which chronic inflammation contributes to CKD remain to be elucidated. As macrophages infiltrate and accumulate in the interstitium, pro-fibrotic factors are released locally, promoting the deposition of extracellular matrix proteins such as collagen type I eventually leading to structural changes[14] These structural changes are associated with impaired vaso-contractility and disturbance of the filtrating capacity of the kidney[15]. We hypothesized that a chronic, obesity-enhanced elevation of systemic pro-inflammatory factors would accelerate the appearance and progression of age-associated renal dysfunction To address this hypothesis, in C57BL/6j mice prone to develop age-dependent renal pathologies[19] we established and monitored high fat diet-induced obesity (DIO) for a period of 52 weeks, compared the structural and functional alterations in the kidneys to age-matched low fat diet controls and linked these alterations to local and systemic inflammatory parameters
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