Somatostatin (SS) influences water and electrolyte transport in the kidney and attenuates renal hypertrophy and albuminuria in early diabetic nephropathy. In the immune and gastrointestinal systems, SS acts in an autocrine/paracrine manner. To determine if SS acts in a similar manner in the kidney, we tested renal cells for production of SS mRNA and peptide by reverse transcription and polymerase chain reaction (RT-PCR) and radioimmunoassay(RIA). We found that whole human kidney and cultured human proximal tubular epithelial cells (PTEC) and mesangial cells (MC) express SS mRNA, but not mRNA for vasoactive intestinal peptide (VIP) or neuropeptide Y (NPY). The SS-specific RT-PCR products had predicted cleavage sites for the restriction enzymes Rsa I and Msc I, corroborating that they were derived from genuine SS mRNA. We also found that PTEC and MC secrete SS peptide. PTEC and MC culture supernatants contained, respectively, 148 ± 34 and 112 ± 61 pg/ml (mean ± SEM) of SS-immunoreactivity, compared to 14.3 ± 6.3 and 24.7 ± 16.9 pg/ml in control media (p < 0.05). In contrast, culture supernatants did not contain VIP- or NPY-immunoreactivity. SS production by PTEC was increased when growth promoting supplements in PTEC medium (including insulin and hydrocortisone) were removed, indicating that one or more growth supplements inhibit SS production. Our results imply that SS is part of an intrarenal autocrine/paracrine regulatory pathway that may impact on renal function and growth and modulate the effects of GH, IGF-1, and other peptides in the kidney. Characterization of this pathway may lead to novel methods to alter the course of diabetic nephropathy and other renal diseases.