UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression.
Endocrine pancreas from pregnant rats undergoes several adaptations that comprise increase in β-cell number, mass and insulin secretion, and reduction of apoptosis. Lactogens are the main hormones that account for these changes. Maternal pancreas, however, returns to a nonpregnant state just after the delivery. The precise mechanism by which this reversal occurs is not settled but, in spite of high lactogen levels, a transient increase in apoptosis was already reported as early as the 3rd day of lactation (L3). Our results revealed that maternal islets displayed a transient increase in DNA fragmentation at L3, in parallel with decreased RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation (pAKT), a known prosurvival kinase. Wortmannin completely abolished the prosurvival action of prolactin (PRL) in cultured islets. Decreased pAKT in L3-islets correlated with increased Tribble 3 (TRB3) expression, a pseudokinase inhibitor of AKT. PERK and eIF2α phosphorylation transiently increased in islets from rats at the first day after delivery, followed by an increase in immunoglobulin heavy chain-binding protein (BiP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islets from L3 rats. Chromatin immunoprecipitation (ChIP) and Re-ChIP experiments further confirmed increased binding of the heterodimer ATF4/CHOP to the TRB3 promoter in L3 islets. Treatment with PBA, a chemical chaperone that inhibits UPR, restored pAKT levels and inhibited the increase in apoptosis found in L3. Moreover, PBA reduced CHOP and TRB3 levels in β-cell from L3 rats. Altogether, our study collects compelling evidence that UPR underlies the physiological and transient increase in β-cell apoptosis after delivery. The UPR is likely to counteract prosurvival actions of PRL by reducing pAKT through ATF4/CHOP-induced TRB3 expression.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
Carla R
CR
Bromati
Camilo
C
Lellis-Santos
Tatiana S
TS
Yamanaka
Tatiane C A
TC
Nogueira
Mauro
M
Leonelli
Luciana C
LC
Caperuto
Renata
R
Gorjão
Adriana R
AR
Leite
Gabriel F
GF
Anhê
Silvana
S
Bordin
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D007774:Lactation / Q000502:physiology*; D023421:Models, Animal; D010766:Phosphorylation / Q000502:physiology; D011388:Prolactin / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; D007328:Insulin; C502443:Trib3 protein, rat; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D011388:Prolactin; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt