The c-Jun amino-terminal kinase (JNK) signaling pathway is activated in human kidney diseases and promotes renal injury in experimental glomerulonephritis. In this study, we examined whether JNK signaling plays a role in the development of diabetic nephropathy or in regulating hypertension, which exacerbates diabetic renal injury. METHODS: Diabetes was induced in spontaneously hypertensive rats (SHR) using streptozotocin. At week 16 of diabetes, rats with equivalent hyperglycemia and albuminuria were randomized into groups which received no treatment, vehicle alone or a selective JNK inhibitor (CC-930, 60 mg/kg/bid) for 10 weeks. These rats were assessed for hypertension and progression of renal damage. RESULTS: At week 16, diabetic rats showed increased kidney JNK activation compared with nondiabetic controls. Effective JNK inhibition was demonstrated at week 26 by reductions in c-Jun phosphorylation. CC-930 did not affect blood pressure, kidney hypertrophy, glomerular hyperfiltration, podocyte loss, glomerular fibrosis or tubulointerstitial injury in diabetic SHR. However, CC-930 reduced macrophages and ccl2 mRNA levels in diabetic kidneys. In contrast, CC-930 exacerbated albuminuria at week 26, which was associated with reduced glomerular mRNA levels of the podocyte-specific molecules, nephrin and podocin.