Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease

Abstract

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II–III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-β-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.

PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels

“…Therefore, it is reasonable to speculate that PNPLA3 expression in the kidneys might also be stimulated under conditions of lipid excess and then increase ectopic lipid accumulation in renal mesangial and tubular cells. In addition, renal lipotoxicity can also promote kidney tubular impairment, abnormal albuminuria and glomerulosclerosis, thus causing a progressive decline in kidney function (33)(34)(35)(36).…”

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

“…Previous in vitro experiments showed that high glucose levels induced lipid deposition in renal tubular cells and tubular injury. In addition to the expression of TNF-α, lipid metabolism-associated markers such as adipose differentiation-related protein and sterol regulatory element binding protein-1 were upregulated in renal tubular cells treated with high glucose, which was accompanied by lipid deposition [11]. However, to our knowledge, there has been no report showing the association between ELD and induction of ER stress in the kidney.…”

“…It would also play an important role in the pathogenesis in the kidney as well as in the liver. Indeed, ELD in the renal tubules, associated with diabetes, has been shown to be related with renal tubular injury [11]. We coined the term 'steatonephropathy' to describe such kidney injury associated with ELD.…”

Lespedeza bicolor Extract Ameliorated Renal Inflammation by Regulation of NLRP3 Inflammasome-Associated Hyperinflammation in Type 2 Diabetic Mice

“…In the present study, a high dose of LBE supplementation declined the level of BUN and serum creatinine, and a low dose of LBE supplementation lowered the ACR. Elevated BUN, serum creatinine, and urine ACR level are well-known markers of renal malfunction with albuminuria [40]. Furthermore, the low dose of LBE supplementation attenuated albuminuria and the high dose of LBE supplementation minimized basement membrane thickening in diabetic kidney morphology.…”