Podocyte-specific knockin of PTEN protects kidney from hyperglycemia.

Huizhen Wang,Feng Wen,Sheng Li,Shuangxin Liu,Wei Shi,Menglei Jv,Ziwei Feng,Tiantian Liang,Yanhui Wang,Ruizhao Li,Zhilian Li,Yangyang Zuo,Xinling Liang,Jing Li,Jianteng Xie,Bin Zhang,Wenjian Wang

doi:10.1152/ajprenal.00575.2017

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

Highlights

Diabetic kidney disease (DKD), a common and severe complication of diabetes mellitus (DM), is believed to be the major cause of end-stage renal disease globally [38]
The current study demonstrated that PTEN was downregulated in DKD in podocytes in both human subjects and diabetic mice
The underlying renoprotection mechanism of PTEN in podocytes was partly associated with the improvement of autophagy and motility, and the inhibition of apoptosis in high glucose (HG)

Summary

Introduction

Diabetic kidney disease (DKD), a common and severe complication of diabetes mellitus (DM), is believed to be the major cause of end-stage renal disease globally [38]. Up to 40% of patients with Type 2 diabetes mellitus develop DKD, contributing to increased morbidity and mortality, as well as the increased economic cost [1, 11]. Podocyte injury, including effacement of podocyte foot processes, detachment, and apoptosis, has proven to be a vital hallmark of triggering DKD under hyperglycemia, with the initial manifestation of albuminuria [31]. Limited treatment has proven to be effective to prevent the initiation and progression of DKD, multiple studies have focused on its molecular mechanism.

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Results

Conclusion