Renalase is emerging as a key player in regulation of cardiovascular diseases. Expressed predominantly in the kidney, this soluble flavoprotein is believed to play a salient role in the cross-talk between the kidney and the sympathetic nervous system, with wide implications ranging from end-stage renal disease to hypertension and cardiac disease. Recent studies by us and others point towards modulation of renalase expression by catecholamines. However, the regulation of renalase expression under catecholamine-excess conditions and the implications of genetic variations in renalase in cardiovascular diseases, remain incompletely understood. In this study, we sought to identify the key regulators of mouse renalase gene expression at the transcriptional and post-transcriptional level. CREB was identified as a crucial transcription factor that dictated renalase expression under both basal and epinephrine-induced conditions. Renalase expression was repressed by miR-29b in vivo, and epinephrine was observed to negatively impact miR-29b expression in vitro, suggesting that the induced expression of renalase was mediated by transcriptional activation and post-transcriptional attenuation. Moreover, we investigated the association of a common renalase promoter SNP -323A>G (rs2576178) with hypertension and acute coronary syndrome in Indian populations. The presence of the G allele enhanced the risk of hypertension by ~1.7-fold (p=0.04) and ~1.6-fold (p=0.01) in geographically-distinct south Indian (n=1113) and north Indian (n=603) populations, respectively. Consistent with this observation, acute coronary syndrome (ACS) patients who harbored the G allele appeared to be at a ~1.8-fold higher risk for ACS in a South Indian cohort (n=1106). Functional studies demonstrate differential promoter activities in different cell lines, suggesting tissue-specific effects on renalase expression. Lymphoblastoid cell lines from the south Asian population harboring these renalase alleles exhibited differential effects on renalase expression. In silico analysis predicted differential binding of several transcription factors (viz. CREB, STAT3, Sp1, HIF1α and NF-ƙB) to these alleles. Of these, CREB demonstrated consistent differences in the activation of renalase promoter harboring the A or G alleles, suggesting a salient role for CREB in the differential expression of renalase gene driven by -323A>G variation. To our knowledge, this is the first study to explore the pathophysiological role of renalase genetic variation in Indian populations and has clinical implications in cardiovascular disease states involving excess catecholamines.