The Sagan Tosu centreback miscontrolled a pass in the 34th minute which allowed Edinson Cavani to open the scoring, with the 23-year-old then dallying over a clearance and allowing Abel Hernandez to double the lead in the 73rd.
“Uruguay are a very strong team so you can’t afford to make mistakes against them,” Aguirre was quoted as saying by Kyodo.
“We made two defensive mistakes and that decided the match tonight.”
Sakai was one of a number of changes that Mexican made to the Japanese line-up as he attempted to shake up a side that woefully underperformed at the World Cup in June.
Their group stage exit led to the resignation of the attack-minded Alberto Zaccheroni and the introduction of the more cautious Aguirre, who cast away a number of the World Cup strugglers.
The Mexican opted for a back four and played defender Masato Morishige in an unfamiliar defensive midfield position, with playmaker Keisuke Honda starting down the left and taking over the captaincy in the absence of Makoto Hasebe.
Another Aguirre debutant, Yusuke Minagawa, came close to giving the former Atletico Madrid coach the perfect start but the Sanfrecce Hiroshima striker could only aim his free header from eight yards out over the bar in the 17th minute.
The miss proved costly as Sakai’s heavy touch was picked up by Cavani who was then put through by Diego Rolan to finish past Eiji Kawashima after the ball deflected off the rookie Japanese defender and over the goalkeeper.
The home side were lacking some creative flair as Uruguay, without suspended striker Luis Suarez and injured coach Oscar Tabarez who stayed home after a back operation last month, kept the hosts comfortably at bay.
The visitors then profited from another mistake by Sakai as Nicolas Lodeiro’s shot was parried by Kawashima but the defender tried to take a touch instead of hook clear and the ball squirmed to Hernandez, who swiftly knocked it through the keeper’s legs.
FC Tokyo striker Yoshinori Muto came on as a late substitute and almost marked his international debut with a sensational strike but his left foot effort from distance hit the inside of the post before bouncing clear.
Aguirre will have a quick chance to rectify the issues when Japan take on Venezuela on Tuesday as they continue the build up to their Asian Cup defence in January in Australia. Venezuela lost 3-1 to South Korea on Friday.
(Writing by Patrick Johnston in Singapore; editing by Justin Palmer)