Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats
Authors: Varanuj Chatsudthipong
Anchalee Pongchaidecha
Lisa Chatsudthipong
Anusorn Lungkaphin
Phatchawan Arjinajarn
Chutima Srimaroeng
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: Organic anion transporter 3; Oat3; insulin signaling; renal function; diabetes
Affiliations: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand., Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand., Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Abstract:  Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway. 

Retracted: Yes

PubPeer comments:
 2018 retraction. http: journals.plos.org plosone article?id=10.1371 journal.pone.0202898 , 
 The retraction notice reads:  Concerns were raised about similarities between the following figure panels in this PLOS ONE article [1] and some of the same authorsu2019 prior publication in the American Journal of the Medical Sciences [2]: Figure 2A [1], u03b2-actin blot lanes 2, 3, and Figure 4C [2], u03b2-actin blot lanes 1, 2. Figure 2A [1], Oat3 blot lanes 1, 2 and Figure 6C [2], phospho-PKCu03b1 blot lanes 2, 3. Furthermore, the Figure 2C u03b2-actin blot lanes 3, 2 in the PLOS ONE article appear to overlap with the Figure 2A u03b2-actin blot lanes 2, 3 following 180-degree rotation. We also noted potential image irregularities in Figure 2A [1], Na+-K+-ATPase blot lane 1. The corresponding author noted that the image panels for which concerns were raised present images from independent experiments; the original underlying blots are not available. Given specific image details in the above figures and the unavailability of the supporting primary data, the PLOS ONE Editors remain concerned about the noted similarities. In addition, the first three subsections of the Results in [1] show significant overlap with experiments and results previously reported in [2]. While the American Journal of the Medical Sciences article was discussed in the Introduction and Discussion of the PLOS ONE article and cited in the Methods, this overlap was not acknowledged in the Results. , 
 Concerns about Figure 2A and C: * Red arrows: Possible duplication of actin blots with each other, and with that of Figure 4C of Phatchawan A et al., The American Journal of the Medical Sciences 347(3): 221u2013227 (2014). https: doi.org 10.1097 MAJ.0b013e3182831740 ![file] , 
 Figure 2, Oat3 blot lanes 1, 2 with Figure 6C from Phatchawan A et al, phospho-PKCu03b1 blot lanes 2, 3. ![file] ,