Increased macula densa
cyclooxygenase-2 (COX-2) is observed in diabetic rats and may contribute to hyperfiltration states. However, the signals mediating increased COX-2 expression in diabetic rats remain undetermined. We recently found that non-proteolytic activation of
prorenin by site-specific
binding proteins, such as
prorenin receptor, plays a pivotal role in the development of
diabetic nephropathy. The present study was designed to determine the contribution of
prorenin receptor to renal cortical COX-2 expression. The COX-2
mRNA and
protein levels of six 4-week-old male wild-type rats and six human
prorenin receptor gene-transgenic (hProRenRcTg) rats were measured by real-time polymerase chain reaction methods, Western blotting, and immunohistochemistry, and compared. There were no differences between the two groups in arterial pressure measured by telemetry, urinary
sodium excretion, or renal levels of rat
prorenin receptor mRNA. The renal cortical COX-2
mRNA levels of the hProRenRcTg rats were significantly higher than those of the wild-type rats, and the renal cortical COX-2
protein levels were also higher in hProRenRcTg rats than in the wild-type rats. Immunohistochemical analysis revealed that COX-2 immunostaining was predominantly present in the macula densa cells, and significantly more COX-2-positive cells were present in the hProRenRcTg rats than in the wild-type rats. In addition, COX-2 inhibition with
NS398 significantly decreased renal cortical blood flow in the hProRenRcTg rats but not in the wild-type rats. These results strongly suggest that human
prorenin receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression.