Answer by Japanese teacher
“What’s up?” is a casual greeting commonly used by young people or guys in America. There is no specific expression for “what’s up” in Japanese. However, as this is originally a casual greeting, the Japanese version would also be casual in nature.
If you are saying it as a form of greeting, you can use Genki? The response to this is “元気(げんき)だよ。Genki dayo” (I’m fine).
If your friend seems to have something in mind and you want to show your concern, you can say Chooshi (wa) doo?