Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats

This study describes elevated histochemical signals for nitric oxide synthase-1 (NOS1) and cyclooxygenase-2 (COX-2) in juxtaglomerular apparatus (JGA) and adjacent thick ascending limb of the kidney of fawn-hooded hypertensive rats (FHH). Two different age groups of FHH (8 and 16 wk; FHH8 and FHH16, respectively) were compared with genetically related fawn-hooded rats with normal blood pressure (FHL) that served as controls. Histopathological changes in FHH comprised focal segmental glomerulosclerosis (FSGS), focal matrix overexpression, and a moderate arteriolopathy with hypertrophy of the media, enhanced immunoreactivity for α-smooth muscle actin, and altered distribution of myofibrils. Macula densa NOS activity, as expressed by NADPH-diaphorase staining, and NOS1 mRNA abundance were significantly elevated in FHH8 (+153 and +88%; P < 0.05) and FHH16 (+93 and +98%; P < 0.05), respectively. Even higher elevations were registered for COX-2 immunoreactivity in FHH8 (+166%; P < 0.05) and FHH16 (+157%; P < 0.05). The intensity of renin immunoreactivity and renin mRNA expression in afferent arterioles was also elevated in FHH8 (+51 and +166%; P < 0.05) and FHH16 (+105 and +136%; P < 0.05), respectively. Thus we show that coordinate upregulation of tubular NOS1, COX-2, and renin expression precedes, and continues after, the manifestation of glomerulosclerotic damage in FHH. These observations may have implications in understanding the role of local paracrine mediators in glomerular disease.