Deposition of hyaluronan has been implicated in the pathogenesis of diabetic glomerulosclerosis. We hypothesized the involvement of hyaluronan in diabetic tubulointerstitial fibrosis. We investigated high-glucose effect on hyaluronan production by rat renal interstitial fibroblasts (normal rat kidney [NRK] cells) and examined the role of hyaluronan in NRK cell proliferation. The involvement of protein kinase C (PKC) and transforming growth factor-beta (TGF-beta) in this response was also examined. After 24 hours of incubation in medium containing 25.6 mmol/L glucose, production of hyaluronan by NRK cells was significantly increased compared with medium containing 5.6 mmol/L glucose (P <.01). L-glucose and mannitol had no effect on hyaluronan production. High glucose enhanced basal in situ PKC activity (P <.01), and both an activator of PKC (phorbol 12-myristate 13-acetate; [PMA]) and TGF-beta 1 were able to increase hyaluronan production by NRK cells (P <.01). The effect of high glucose on hyaluronan production was diminished by coincubating cells with PKC inhibitors (staurosporine [Stp] or calphostin C [CpC]) or with an anti-TGF-beta neutralizing antibody. Stimulation of hyaluronan production by PMA was also normalized by anti TGFbeta neutralizing antibody, but the effect of TGF-beta1 was not affected by inhibition of PKC. Finally, incubating quiescent NRK cells with 50 or 100 ng/mL hyaluronan for 24 hours significantly increased NRK cell number (P <.01). In conclusion, high glucose stimulates hyaluronan production through the PKC/TGF-beta cascade. Increased hyaluronan promotes NRK cell proliferation. These results suggest that hyaluronan may play a role in the pathogenesis of interstitial fibrosis in diabetic kidney disease.
Copyright 2001 by W.B. Saunders Company