Diabetic nephropathy (DN) is a microvascular complication caused by diabetes mellitus, which often leads to structural and functional damages of several kidney cell types, and has become an important cause of chronic kidney disease and end-stage renal disease. Connexins are involved in maintaining cell function and tissue homeostasis in various organs by forming semi-channels and mediating gap-junctional intercellular communication. Connexin 43 (Cx43) is the most abundant and widely studied connexin in kidney. Accumulating evidences have shown that Cx43 is involved in the pathological process associated with glomerular mesangial cells, podocytes and renal tubular epithelial cells during the development of DN. However, the molecular mechanism of Cx43 in regulating kidney cell homeostasis of DN is still unclear. The paper systematically reviews the relationship between Cx43 and pathogenesis of DN from the perspective of signaling pathway regulation, and explores the therapeutic potential of targeting Cx43 in the intervention of DN.