title: Implication of CD38 gene in podocyte epithelial-to-mesenchymal transition and glomerular sclerosis.
abstract: CD38 is a multifunctional protein involving in a number of signalling pathways. Given that the lack of CD38 is considered as a dedifferentiation marker of lymphocytes and other cells, we hypothesized that CD38 and its signalling pathway may participate in the epithelial-to-mesenchymal transition (EMT) process of podocytes and thereby regulates the integrity of glomerular structure and function. Western blot analysis and RT-PCR demonstrated that renal tissue CD38 expression was lacking in CD38(-/-)  mice or substantially reduced in renal CD38 shRNA-transfected WT (CD38-shRNA) mice compared to CD38(+/+)  littermates. Confocal fluorescent microscopy demonstrated the reduced expression of epithelial markers (P-Cadherin, ZO-1 and podocin) and increased expression of mesenchymal markers (FSP-1, α-SMA and desmin) in the glomeruli of CD38(-/-)  and CD38-shRNA mice compared to CD38(+/+)  mice. Morphological examinations showed profound injury in the glomeruli of CD38(-/-)  or CD38-shRNA mice compared to CD38(+/+)  mice. This enhanced glomerular injury in CD38(-/-)  or CD38-shRNA mice was accompanied by increased albuminuria and proteinuria. DOCA/high salt treatment further decreased the expression of epithelial markers and increased the abundance of mesenchymal markers, which were accompanied by more increased glomerular damage index and mean arterial pressure in CD38(-/-)  and CD38-shRNA mice than CD38(+/+)  mice. In vitro studies showed that inhibition of CD38 enhances the EMT in podocytes. In conclusion, our observations reveal that the normal expression of CD38 importantly contributes to the differentiation and function of podocytes and the defect of this gene expression may be a critical mechanism inducing EMT and consequently resulting in glomerular injury and sclerosis.
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Krishna M
authors: KM
authors: Boini
authors: Min
authors: M
authors: Xia
authors: Jing
authors: J
authors: Xiong
authors: Caixia
authors: C
authors: Li
authors: Lori P
authors: LP
authors: Payne
authors: Pin-Lan
authors: PL
authors: Li
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D062186:Arterial Pressure; D015415:Biomarkers / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D003900:Desoxycorticosterone; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D012598:Sclerosis; D012965:Sodium Chloride; D014162:Transfection
chemical_list: D015415:Biomarkers; D003893:Desmin; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D034741:RNA, Small Interfering; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1