Genetic or Pharmacologic Blockade of EGFR Inhibits Renal Fibrosis

Liu, Na; Guo, Jian‐Kan; Pang, Maoyin; Tolbert, Evelyn; Ponnusamy, Murugavel; Gong, Rujun; Bayliss, George; Dworkin, Lance D.; H, Yan; Zhuang, Songlin

doi:10.1681/asn.2011050493

Cited by 142 publications

(159 citation statements)

References 42 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…1 Our previous studies in a UUO model demonstrated that EGFR activation contributes to a proinflammatory response and infiltration of inflammatory cells into the interstitium. 46 In the current study, inhibition of EGFR with gefitinib also reduced macrophage infiltration and expression of multiple proinflammatory cytokines/chemokines, including TNF-a, IL-6, MCP-1, and RANTES, in the kidney of hyperuricemic rats. Moreover, EGFR inactivation resulted in a decrease in renal phosphorylation of NF-kB induced by hyperuricemia.…”

Section: Discussionsupporting

confidence: 57%

See 1 more Smart Citation

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

Liu¹,

Wang²,

Yang

et al. 2015

Journal of the American Society of Nephrology

Self Cite

104

141

View full text Add to dashboard Cite

Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-b1 and NF-kB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-b1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body. Serum uric acid is enhanced in patients with CKD regardless of whether it is primary or secondary. Hyperuricemia-related diseases were historically viewed with limited interest. 1 However, increasing evidence has indicated that the increased level of uric acid is tightly associated with the development and progression of CKD as well as many other diseases, such as hypertension, cardiovascular diseases, and diabetes. [2][3][4][5][6][7] For example, a recent meta-analysis of a prospective cohort study showed a 12% rise in mortality for every 1-mg/dl rise in serum uric acid in persons with coronary heart disease. 8 Other pilot investigations indicate that lowering plasma uric acid concentrations slows and delays the development of CKD. [9][10][11][12][13][14][15] Thus, uric acid is likely an important mediator and risk marker in CKD.Uric acid is the final metabolic product of purine metabolism in humans and is excreted in urine. Serum uric acid levels are controlled by the balance of

show abstract

Section: Discussionsupporting

confidence: 57%

“…46 The densitometry analysis of immunoblot results was conducted using ImageJ software (National Institutes of Health, Bethesda, MD).…”

Section: Immunoblot Analysismentioning

confidence: 99%

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

Liu¹,

Wang²,

Yang

et al. 2015

Journal of the American Society of Nephrology

Self Cite

104

141

View full text Add to dashboard Cite

show abstract

“…15,16,32,33 In this regard, we recently reported that in a model of accelerated diabetic nephropathy (endothelial nitric oxide synthase-streptozotocin mice), administration of the EGFR tyrosine kinase inhibitor, erlotinib, markedly reduced albuminuria and glomerulosclerosis. 20 Similarly, studies in diabetic rats reported that a different EGFR tyrosine kinase inhibitor, PKI 166, attenuated early glomerular enlargement and preserved podocytes.…”

Section: Discussionmentioning

confidence: 99%

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

115

114

View full text Add to dashboard Cite

The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR podKO ) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR podKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR podKO diabetic mice had less TGF-b1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR podKO diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-b1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-b1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.

show abstract

“…Boosting survival and regeneration of TECs might be renoprotective and antifibrotic as, for example, suggested for CSF-1 (143). Other TECs factors driving fibrosis include Notch (144), lipocalin-2 (NGAL) (28), kidney injury molecule-1 (KIM-1) (145), b-catenin signaling (146), and the EGFR (147,148). Paracrine signaling from damaged TECs is probably one of a major mechanisms driving renal fibrosis ( Figure 3).…”

Section: The Role Of Glomerular Cellsmentioning

confidence: 98%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

View full text Add to dashboard Cite

Genetic or Pharmacologic Blockade of EGFR Inhibits Renal Fibrosis

Cited by 142 publications

References 42 publications

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Contact Info

Product

Resources

About