Inflammatory stress exacerbates lipid accumulation and podocyte injuries in diabetic nephropathy

Zhang, Yang; Ling, Kun; Liu, Jing; Wu, Yu; Hu, Ze Bo; Liu, Liang; Lü, Jian; Zhang, Xiao Liang; Liu, Bi Cheng

doi:10.1007/s00592-015-0753-9

Cited by 47 publications

(39 citation statements)

References 27 publications

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“…Although it is known that serum retinol concentrations are increased in patients with CKD, 48 scant data are currently available on the regulation of lipid and retinol metabolism in renal podocytes 46,47 . However, recent data suggest that podocytes can accumulate lipid droplets, and that this process is associated with activation of the inflammasome and is involved in the pathogenesis of glomerulopathy associated with T2DM and obesity 24,49‐51 . Consistently with decreased retinol bioavailability in pericytes carrying the PNPLA3 I148M variant, 43‐45 it has been reported that a highly selective agonist for retinoic acid receptor β2 (ie AC261) was able to ameliorate diabetic nephropathy in an experimental mouse model 52 .…”

Section: Discussionmentioning

confidence: 97%

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

Mantovani

Taliento

Zusi

et al. 2020

Liver International

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Background and Aims:Emerging evidence suggests an association between patatinlike phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods:We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73 m 2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results:In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m 2 , P = .0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P = .028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P < .0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P = .008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions:The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes. | 1131 MANTOVANI eT Al.

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Section: Discussionmentioning

confidence: 97%

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

Mantovani

Taliento

Zusi

et al. 2020

Liver International

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“…Our previous studies demonstrated that inflammatory responses played important roles in renal injury . Inflammatory cytokines such as iNOS, IL6, TNF‐α and ETA played important roles in the pathological process of renal injury .…”

Section: Discussionmentioning

confidence: 98%

“…Our previous studies demonstrated that inflammatory responses played important roles in renal injury. [18][19][20] Inflammatory cytokines such as iNOS, IL6, TNF-a and ETA played important roles in the pathological process of renal injury. [21,22] The protein expressions of iNOS, IL6, TNF-a and ETA increased significantly in the renal tissue of DN model rats and were inhibited by enzastaurin.…”

Section: Discussionmentioning

confidence: 99%

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

Cheng

Chao

Chen

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). p66shc is closely related to oxidative stress. However, the exact mechanism of its involvement in diabetic nephropathy is poorly understood. This study aimed to investigate the role of the p66shc‐related pathway in diabetic nephropathy. Methods In an in‐vivo experiment, rats were injected with streptozotocin to induce early diabetic nephropathy. The treatment groups were an aminoguanidine group and an enzastaurin group. In an in‐vitro experiment, human renal proximal tubule epithelial cells (HK‐2 cells) were cultured and incubated with high glucose. Key findings Upregulated protein expression of p66shc and p‐p66shc was found in vivo and in vitro when cells were stimulated by high levels of glucose; this effect was accompanied by enhanced oxidative stress and damaged renal function, both of which were alleviated by p66shc siRNA. p66shc regulated NADPH oxidase, further promoting activation of oxidative stress. As an inhibitor of PKCβ, enzastaurin reduced the abnormal expression of p66shc and NADPH oxidase and alleviated renal injury. Conclusions This study demonstrated enzastaurin alleviated diabetic renal injury via modulation of the PKCβ‐p66shc‐NADPH oxidase pathway, which provided a new perspective for the treatment of early DN.

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“…It is suggested that the low-density lipoprotein may increase the expression of TNF- α in mesangial cells, while the inflammatory cytokines contribute to lipid-mediated renal damage [22]. Some studies have also shown that the inflammation will induce lipid accumulation which contributed to podocyte injury and accelerate the progression of DKD [23]. Therefore, the renoprotective effect of SYFSF is at least partially attributed to breaking the vicious circle between inflammatory response and dyslipidemia by inhibiting the TNF- α /NF- κ B pathway.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective Effect of the Shen-Yan-Fang-Shuai Formula by Inhibiting TNF-α/NF-κB Signaling Pathway in Diabetic Rats

Wang

et al. 2017

Journal of Diabetes Research

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Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF's renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

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Inflammatory stress exacerbates lipid accumulation and podocyte injuries in diabetic nephropathy

Abstract: Inflammation induced lipid accumulation and the EMT of podocytes through the dysregulation of the LDLr pathway, which contributed to podocyte injury and accelerated the progression of DN.

Cited by 47 publications

References 27 publications

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

Renoprotective Effect of the Shen-Yan-Fang-Shuai Formula by Inhibiting TNF-α/NF-κB Signaling Pathway in Diabetic Rats

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