The turnover and repair of peritubular capillaries is essential for the maintenance of normal renal tubular structure and function. Following injury, ineffective capillary repair/ angiogenesis may result in chronic disease, whereas effective repair attenuates the injury process. Thus, the process of healing in the kidney is likely dependent on an intricate balance between angiogenic and anti-angiogenic factors to maintain the renal microvasculature. We investigated the role of cytoprotective heme oxygenase-1 (HO-1) in the regulation of chemokines in human renal proximal tubular epithelial cells (RPTEC). Transfection of RPTEC with a HO-1 overexpression plasmid, promoted a marked induction in the mRNA expression of the anti-angiogenic chemokine CXCL10, along with angiogenic chemokines CXCL8 and CCL2. Utilizing a CXCL10 promoter-luciferase construct, we observed that HO-1-induced CXCL10 expression is regulated at the transcriptional level. However, with increase in concentrations and time intervals of HO-1 induction, there was marked decrease in CXCL10 expression. Using pharmacological inhibitors, we found that HO-1-induced early robust CXCL10 transcription is mediated through the PKC signaling pathway. To evaluate the functional significance of HO-1-induced CXCL10 release, we cultured human vascular endothelial cells (EC) in absence/presence of culture supernatants of the HO-1 plasmid-transfected RPTEC. We found that the early (24 hr) supernatants of the HO-1 plasmid-transfected cells (RPTEC) inhibited EC proliferation; and this effect was blocked by addition of a CXCL10 neutralizing antibody. Thus, HO-1 can regulate the expression of the anti-angiogenic CXCL10, and may alter a critical balance between angiogenic versus anti-angiogenic factors that are important to maintain renal microvasculature during injury.