Angiotensin ii type 2 receptor agonist, compound 21, prevents tubular epithelial cell damage caused by renal ischemia

FERNANDA, FUSSI MARÍA; FLORENCIA, HIDALGO; GABRIEL, BUONO; BEATRIZ, MARQUEZ SUSANA; ALEJANDRO, PARIANI; LUIS, MOLINAS JORGE; CECILIA, LAROCCA MARÍA; ALICIA, MONASTEROLO LILIANA; MARÍA, MOLINAS SARA

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2021 vol. 194

0006-2952

During ischemic acute kidney injury (AKI), loss of cytoskeletal integrity and disruption ofintercellular junctions are rapid events in response to ATP depletion. Angiotensin II type 2receptor (AT2R) is overexpressed in injury situations and its stimulation by angiotensin II(AngII) is related to beneficial renal effects. Its role on ischemic AKI has not been deeplystudied. The aim of the present study was to investigate whether pretreatment with the AT2Ragonist, C21, prevents ischemic renal epithelial cell injury. Studies in a model of 40 min ofrenal ischemia followed by 24 h of reperfusion (IR) in rats demonstrated that C21pretreatment attenuated renal dysfunction and induced better preservation of tubulararchitecture. In addition, we studied the expression of Rho GTPases, RhoA and Cdc42, sincethey are key proteins in the regulation of the actin cytoskeleton and the stability of epithelialintercellular junctions. IR downregulated RhoA and Cdc42 abundance in rat kidneys. C21pretreatment prevented RhoA reduction and increased Cdc42 abundance compared tocontrols. We also used an in vitro model of ATP depletion in MDCK cells grown on filtersupport. Using immunofluorescence we observed that in MDCK cells, C21 pretreatmentprevented the ATP depletion-induced reduction of actin in brush border microvilli and instress fibers. Moreover, C21 prevented membrane E-cadherin reduction, and RhoA andCdc42 downregulation. The present study describes for the first time a renoprotective effectof the AT2R agonist, C21, against AKI, and provides evidence supporting that stimulation ofAT2R triggers cytoprotective mechanisms against an ischemic event.