Oestrogen inhibits PTPRO to prevent the apoptosis of renal podocytes

Abstract

Podocytes are a major component of the glomerular filtration membrane, and their apoptosis is involved in a variety of nephrotic syndromes. In the current study, the effects and molecular mechanisms of oestrogen on the proliferation and apoptosis of podocytes were investigated to elucidate the role of oestrogen in the pathogenesis of childhood nephrotic syndrome. The cell proliferation of mouse renal podocytes (MPC-5) and human primary renal podocytes was promoted by 17β-oestradiol (E2) in what appear to be a time-dependent manner. Apoptosis was inhibited by E2 and promoted by the E2 antagonist, tamoxifen. The expression of protein tyrosine phosphatase receptor type O (PTPRO) decreased with the increasing dosage of E2, but increased with the increasing dosage tamoxifen in MPC-5 and human podocytes. The protein, oestrogen receptor (ER)α, was not expressed in MPC-5 and human podocytes. E2 binding to ERβ completely eliminated PTPRO expression in MPC-5. In podocytes, PTPRO was phosphorylated by E2 at the Y1007 and associated with tyrosine-protein kinase JAK2 (JAK2) activation, rather than JAK1 activation. PTPRO was involved in the binding of E2 to signal transducer and activator of transcription (STAT)3 at the Y705 and S727 sites, resulting in the phosphorylation of STAT3 in podocytes. Through PTPRO, E2 also regulated the proliferation and apoptosis of podocytes. In conclusion, oestrogen binding to ERβ, rather than ERα, promoted the proliferation of podocytes and inhibited the apoptosis of podocytes by inhibiting the expression of PTPRO. The mechanism may be associated with the activation of the JAK2/STAT3 signalling pathway. The current study may provide a novel direction for the treatment of childhood nephrotic syndrome.

PTPRO predicts patient prognosis and correlates with immune infiltrates in human clear cell renal cell carcinoma

“…To explore the role of PTPRO in cancers, we first characterized the expression of PTPRO in different human tissues using the data obtained from The GTEx database ( www.gtexportal.org ) ( 19 ), via the Human Protein Atlas ( www.proteinatlas.org ). We found that PTPRO abundance was highest in the kidney ( Figure 1A ), supporting a critical physiological role of PTPRO in the kidney, as previously reported ( 7 ). Notably, all of 17 analyzed renal cancer cell lines had lower expression of PTPRO than the normal kidney tissues (MERAV database, merav.wi.mit.edu) ( 20 ) (P<0.001 for all, Figure 1B ).…”

“…Protein tyrosine phosphatase receptor type O (PTPRO), a member of receptor-type PTP of the R3 subtype (4), was initially identified as a podocyte-specific protein that might regulate glomerular structure and function (7)(8)(9). PTPRO was demonstrated to participate in multiple cellular and physiological functions, including synapse formation, neuron differentiation, and podocyte proliferation (7,9,10). Recently, PTPRO has been assumed to act as a putative tumor suppressor in several cancer types (6,(11)(12)(13).…”

PTPRO knockdown protects against inflammation in hemorrhage shock-induced acute lung injury involving the NF-κB signaling pathway

“…According to the previous study, PTPRO aggravates atherosclerosis by promoting oxidative stress and cell apoptosis induced by oxidized low-density lipoprotein [10]. Oestrogen restricts renal podocyte apoptosis by inhibiting PTPRO [11]. Besides, PTPRO is a candidate tumor suppressor in human lung cancer and downregulation of PTPRO mediated by miR-6803-5p promotes the proliferation and invasion of the cancer cells in colorectal cancer [12,13].…”

Estrogen and estrogen receptors in kidney diseases

“…For example, estrogen could increase the degradation of ECM to slow the progression of DKD through upregulating MMP-9 in MCs [ 213 ]. It also inhibited podocyte apoptosis through binding to ERβ, which was associated with the activation of the JAK2/STAT3 signaling pathway [ 214 ]. Moreover, estrogen or tamoxifen could improve albumin excretion, reduce glomerular size, and decrease matrix accumulation via upregulating the expression of ERβ and downregulating TGF-β in podocytes from db/db mice [ 215 ].…”