The NF-κB pathway plays an important role in chronic inflammatory and
autoimmune diseases. Recently, NF-κB has also been suggested as an important mechanism linking
obesity,
inflammation, and metabolic disorders. However, there is no current evidence regarding the mechanism of action of NF-κB inhibition in
insulin resistance and
diabetic nephropathy in type 2 diabetic animal models. We investigated the effects of the NF-κB inhibitor
celastrol in db/db mice. The treatment with
celastrol for 2 months significantly lowered fasting plasma
glucose (FPG), HbA1C and homeostasis model assessment index (HOMA-IR) levels.
Celastrol also exhibited significant decreases in
body weight, kidney/
body weight and adiposity.
Celastrol reduced
insulin resistance and
lipid abnormalities and led to higher plasma
adiponectin levels.
Celastrol treatment also significantly mitigated
lipid accumulation and oxidative stress in organs including the kidney, liver and adipose tissue. The treated group also exhibited significantly lower
creatinine levels and urinary
albumin excretion was markedly reduced.
Celastrol treatment significantly lowered mesangial expansion and suppressed
type IV collagen,
PAI-1 and TGFβ1 expressions in renal tissues.
Celastrol also improved abnormal lipid metabolism, oxidative stress and proinflammatory
cytokine activity in the kidney. In cultured podocytes,
celastrol treatment abolished
saturated fatty acid-induced proinflammatory
cytokine synthesis. Taken together,
celastrol treatment not only improved
insulin resistance,
glycemic control and oxidative stress, but also improved renal functional and structural changes through both metabolic and anti-inflammatory effects in the kidney. These results suggest that targeted
therapy for NF-κB may be a useful new therapeutic approach for the management of type II diabetes and
diabetic nephropathy.