Growth hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of gh with implications for the pathogenesis of diabetic nephropathy.
Growth hormone (GH) excess results in structural and functional changes in the kidney and is implicated as a causative factor in the development of diabetic nephropathy (DN). Glomerular podocytes are the major barrier to the filtration of serum proteins, and altered podocyte function and/or reduced podocyte number is a key event in the pathogenesis of DN. We have previously shown that podocytes are a target for GH action. To elucidate the molecular basis for the effects of GH on the podocyte, we conducted microarray and RT-quantitative PCR analyses of immortalized human podocytes and identified zinc finger E-box-binding homeobox 2 (ZEB2) to be up-regulated in a GH dose- and time-dependent manner. We established that the GH-dependent increase in ZEB2 levels is associated with increased transcription of a ZEB2 natural antisense transcript required for efficient translation of the ZEB2 transcript. GH down-regulated expression of E- and P-cadherins, targets of ZEB2, and inhibited E-cadherin promoter activity. Mutation of ZEB2 binding sites on the E-cadherin promoter abolished this effect of GH on the E-cadherin promoter. Whereas GH increased podocyte permeability to albumin in a paracellular albumin influx assay, shRNA-mediated knockdown of ZEB2 expression abrogated this effect. We conclude that GH increases expression of ZEB2 in part by increasing expression of a ZEB2 natural antisense transcript. GH-dependent increase in ZEB2 expression results in loss of P- and E-cadherins in podocytes and increased podocyte permeability to albumin. Decreased expression of P- and E-cadherins is implicated in podocyte dysfunction and epithelial-mesenchymal transition observed in DN. We speculate that the actions of GH on ZEB2 and P- and E-cadherin expression play a role in the pathogenesis of microalbuminuria of DN.
Kumar
P Anil
PA
Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Kotlyarevska
Kateryna
K
Dejkhmaron
Prapai
P
Reddy
Gaddameedi R
GR
Lu
Chunxia
C
Bhojani
Mahaveer S
MS
Menon
Ram K
RK
D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D016372:RNA, Antisense / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2
D015820:Cadherins; D018398:Homeodomain Proteins; D016372:RNA, Antisense; D012097:Repressor Proteins; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D019382:Human Growth Hormone