Inflammatory stress promotes the development of obesity-related chronic kidney disease via CD36 in mice

Abstract

Ectopic fat located in the kidney has emerged as a novel cause of obesity-related chronic kidney disease (CKD). In this study, we aimed to investigate whether inflammatory stress promotes ectopic lipid deposition in the kidney and causes renal injury in obese mice and whether the pathological process is mediated by the fatty acid translocase, CD36. High-fat diet (HFD) feeding alone resulted in obesity, hyperlipidemia, and slight renal lipid accumulation in mice, which nevertheless had normal kidney function. HFD-fed mice with chronic inflammation had severe renal steatosis and obvious glomerular and tubular damage, which was accompanied by increased CD36 expression. Interestingly, CD36 deficiency in HFD-fed mice eliminated renal lipid accumulation and pathological changes induced by chronic inflammation. In both human mesangial cells (HMCs) and human kidney 2 (HK2) cells, inflammatory stress increased the efficiency of CD36 protein incorporation into membrane lipid rafts, promoting FFA uptake and intracellular lipid accumulation. Silencing of CD36 in vitro markedly attenuated FFA uptake, lipid accumulation, and cellular stress induced by inflammatory stress. We conclude that inflammatory stress aggravates renal injury by activation of the CD36 pathway, suggesting that this mechanism may operate in obese individuals with chronic inflammation, making them prone to CKD.

Dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats

“…Chronic inflammation has recently been shown to promote ectopic lipid deposition in the kidney in obese mice . The resulting tissue lipid accumulation in turn triggers inflammation and the release of multiple inflammatory factors, causing oxidative injury and structural changes, which further aggravate kidney injury and dysfunction .…”

“…Interestingly, a recent study has shown the role of inflammation in kidney disease in the development of kidney lipid accumulation in obese mice. The inflammation releases multiple inflammatory cytokines, causing oxidative injury and structural changes that further aggravate renal injury . In addition, lipids or their breakdown products in non‐adipose tissue, also produce the key profibrotic factor, transforming growth factor‐β1 (TGF‐β1), which causes a fibrotic response, subsequently leading to organ dysfunction .…”

Inhibition of Inflammatory Cytokine Expression Prevents High-Fat Diet-Induced Kidney Injury: Role of Lingonberry Supplementation

“…The pathophysiology of CKD is complex and incompletely understood. Several mechanisms by which obesity causes CKD have been proposed, which include renal lipid accumulation, inflammation and mitochondrial dysfunction (5,7,8). Chronic inflammatory response has been implicated as one of the important mediators contributing to kidney injury in patients with obesity (9).…”

The C18:3n6/C22:4n6 ratio is a good lipid marker of chronic kidney disease (CKD) progression

“…Inflammatory stress enhances kidney damage through the activation of the CD36 pathway. This mechanism may occur in obese people with chronic inflammation, which makes them susceptible to CKD [6]. It seems that increased fat content in liver is linked to increased occurrence of mild and heavy albuminuria and decreased glomerular filtration rate (GFR).…”