For the first time, the authors report an intimate link between kidney and heart functions as it pertains to the regulation of stress protein gene expression in the heart. They show that the stress on the target organ, the kidney, is translated into a response in the cardiovascular system, as reflected by the induction of heme oxygenase (HO)-1 gene expression, which, in turn, may be a cellular defense response as suggested by an increase in cGMP level in the heart, and an increase in the rate of bilirubin formation by the kidney and the heart. HO-1 is a stress protein (HSP32) and, together with HO-2, catalyzes oxidation of the heme molecule to generate CO, a likely signal molecule for the generation of cGMP, and bilirubin, an antioxidant. Specifically, bilateral renal ischemia for 30 min caused a 3-fold increase in the approximately 1.8-kb HO-1 mRNA in the heart within 4 h after reperfusion and remained essentially at this level for 24 h, at which point, a 2.6-fold increase in HO-1 mRNA in the descending aorta was also detected. Heart HO-1 mRNA remained elevated for more than 48 h; in contrast, at the 48-h time point, the transcript level in the kidney, which had increased by 10-fold 24 h after reperfusion, had returned to the control level. Neither in the heart nor in the kidney did HO-2 transcripts (approximately 1.3 and 1.9 kb) respond to renal ischemia/ reperfusion. The increase in heart HO-1 transcript level was accompanied by an increase in HO-1 protein, as judged by Western blot and immunohistochemical analysis, and in enzyme activity, as judged by bilirubin formation. In addition, cGMP concentration in the heart was elevated when measured at 24 h and 48 h after reperfusion of the kidney, in the absence of an increase in the activity of NO. Data suggest that hemodynamic stress caused by the occlusion of the renal artery is responsible for activation of HO-1 gene expression in the heart. An argument is made for the role of HO-1 in the defense mechanisms of the heart pertaining to the enzyme's function in a hemoprotein regulatory capacity, along with the biological activity of its products.