title: Early postnatal hyperalimentation impairs renal function via SOCS-3 mediated renal postreceptor leptin resistance.
abstract: Early postnatal hyperalimentation has long-term implications for obesity and developing renal disease. Suppressor of cytokine signaling (SOCS) 3 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and ERK1/2 and thereby plays a pivotal role in mediating leptin resistance. In addition, SOCS-3 is induced by both leptin and inflammatory cytokines. However, little is known about the intrinsic-renal leptin synthesis and function. Therefore, this study aimed to elucidate the implications of early postnatal hyperalimentation on renal function and on the intrinsic-renal leptin signaling. Early postnatal hyperalimentation in Wistar rats during lactation was induced by litter size reduction at birth (LSR) either to LSR10 or LSR6, compared with home cage control male rats. Assessment of renal function at postnatal day 70 revealed decreased glomerular filtration rate and proteinuria after LSR6. In line with this impairment of renal function, renal inflammation and expression as well as deposition of extracellular matrix molecules, such as collagen I, were increased. Furthermore, renal expression of leptin and IL-6 was up-regulated subsequent to LSR6. Interestingly, the phosphorylation of Stat3 and ERK1/2 in the kidney, however, was decreased after LSR6, indicating postreceptor leptin resistance. In accordance, neuropeptide Y (NPY) gene expression was down-regulated; moreover, SOCS-3 protein expression, a mediator of postreceptor leptin resistance, was strongly elevated and colocalized with NPY. Thus, our findings not only demonstrate impaired renal function and profibrotic processes but also provide compelling evidence of a SOCS-3-mediated intrinsic renal leptin resistance and concomitant up-regulated NPY expression as an underlying mechanism.
authors.affiliation: Department of Pediatrics Adolescent Medicine, University of Cologne, Kerpener Strasse 62, D-50937 Cologne, Germany. miguel.alejandre-alcazar@uk-koeln.de
authors.forename: Miguel Angel Alejandre
authors.initials: MA
authors.lastname: Alcazar
authors.forename: Eva
authors.initials: E
authors.lastname: Boehler
authors.forename: Eva
authors.initials: E
authors.lastname: Rother
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Christina
authors.initials: C
authors.lastname: Vohlen
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Christian
authors.initials: C
authors.lastname: Plank
authors.forename: Jörg
authors.initials: J
authors.lastname: Dötsch
mesh_terms: D000821:Animal Feed; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D007249:Inflammation; D007668:Kidney / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009478:Neuropeptide Y / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020738:Leptin; D009478:Neuropeptide Y; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins