Amelioration of albuminuria in ROCK1 knockout mice with streptozotocin-induced diabetic kidney disease

Li Zhou, Fei Liu, Xiao R. Huang, Fang Liu, Haiyong Chen, Arther C K Chung, Jianjian Shi, Lei Wei, Hui Y. Lan, Ping Fu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background: Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism. Methods: A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined. Results: Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β 1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β 1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells. Conclusion: ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex-megalin/cubilin.

Original languageEnglish
Pages (from-to)468-475
Number of pages8
JournalAmerican Journal of Nephrology
Volume34
Issue number5
DOIs
StatePublished - Nov 2011

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Low Density Lipoprotein Receptor-Related Protein-2
Albuminuria
Diabetic Nephropathies
Streptozocin
Knockout Mice
Transforming Growth Factors
Albumins
rho-Associated Kinases
Interleukin-1
Fibrosis
Epithelial Cells
Kidney
Glucose
Endocytosis
Collagen
Down-Regulation
Cell Line
Injections
intrinsic factor-cobalamin receptor
Genes

Keywords

  • Cubilin
  • Diabetic kidney disease
  • Megalin
  • ROCK
  • Tubular cells, albuminuria

ASJC Scopus subject areas

  • Nephrology

Cite this

Amelioration of albuminuria in ROCK1 knockout mice with streptozotocin-induced diabetic kidney disease. / Zhou, Li; Liu, Fei; Huang, Xiao R.; Liu, Fang; Chen, Haiyong; Chung, Arther C K; Shi, Jianjian; Wei, Lei; Lan, Hui Y.; Fu, Ping.

In: American Journal of Nephrology, Vol. 34, No. 5, 11.2011, p. 468-475.

Research output: Contribution to journalArticle

Zhou, Li ; Liu, Fei ; Huang, Xiao R. ; Liu, Fang ; Chen, Haiyong ; Chung, Arther C K ; Shi, Jianjian ; Wei, Lei ; Lan, Hui Y. ; Fu, Ping. / Amelioration of albuminuria in ROCK1 knockout mice with streptozotocin-induced diabetic kidney disease. In: American Journal of Nephrology. 2011 ; Vol. 34, No. 5. pp. 468-475.
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AU - Zhou, Li

AU - Liu, Fei

AU - Huang, Xiao R.

AU - Liu, Fang

AU - Chen, Haiyong

AU - Chung, Arther C K

AU - Shi, Jianjian

AU - Wei, Lei

AU - Lan, Hui Y.

AU - Fu, Ping

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N2 - Background: Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism. Methods: A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined. Results: Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β 1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β 1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells. Conclusion: ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex-megalin/cubilin.

AB - Background: Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism. Methods: A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined. Results: Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β 1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β 1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells. Conclusion: ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex-megalin/cubilin.

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KW - Diabetic kidney disease

KW - Megalin

KW - ROCK

KW - Tubular cells, albuminuria

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