Berberine Improves Kidney Function in Diabetic Mice via AMPK Activation

Abstract

Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease are required. Berberine (BBR) has several preventive effects on diabetes and its complications. However, the molecular mechanism of BBR on kidney function in diabetes is not well defined. Here, we reported that activation of AMP-activated protein kinase (AMPK) is required for BBR-induced improvement of kidney function in vivo. AMPK phosphorylation and activity, productions of reactive oxygen species (ROS), kidney function including serum blood urea nitrogen (BUN), creatinine clearance (Ccr), and urinary protein excretion, morphology of glomerulus were determined in vitro or in vivo. Exposure of cultured human glomerulus mesangial cells (HGMCs) to BBR time- or dose-dependently activates AMPK by increasing the thr172 phosphorylation and its activities. Inhibition of LKB1 by siRNA or mutant abolished BBR-induced AMPK activation. Incubation of cells with high glucose (HG, 30 mM) markedly induced the oxidative stress of HGMCs, which were abolished by 5-aminoimidazole-4-carboxamide ribonucleoside, AMPK gene overexpression or BBR. Importantly, the effects induced by BBR were bypassed by AMPK siRNA transfection in HG-treated HGMCs. In animal studies, streptozotocin-induced hyperglycemia dramatically promoted glomerulosclerosis and impaired kidney function by increasing serum BUN, urinary protein excretion, and decreasing Ccr, as well as increased oxidative stress. Administration of BBR remarkably improved kidney function in wildtype mice but not in AMPKα2-deficient mice. We conclude that AMPK activation is required for BBR to improve kidney function in diabetic mice.

Renoprotective effects of berberine through regulation of the MMPs/TIMPs system in streptozocin-induced diabetic nephropathy in rats

“…These data suggested that the rat model of DN was successfully established (Betz and Conway, 2014). After treatment with berberine, the physiological indicators in the cases showed varying degrees of improvement (Zhao et al, 2014). The data above also suggested that berberine could not only reduce the blood glucose and urine total protein excretion except for the body weight but also improve the renal pathological changes, such as ECM accumulation, glomerulus atrophy and glomerular sclerosis, thus preventing the progression of DN .…”

Down-Regulation of MicroRNA-137 Improves High Glucose-Induced Oxidative Stress Injury in Human Umbilical Vein Endothelial Cells by Up-Regulation of AMPKα1

“…Some studies showed that AMPK inactivation was linked to low levels of oxidative stress, and that AMPK activation reversed these effects [41,42]. However, other studies demonstrated that AMPK inactivation was closely related to increased oxidative stress, and that AMPK reactivation decreased levels of oxidative stress [22,[43][44][45][46]. In this study, our results showed that HG-induced oxidative stress was closely related to downregulation of AMPKα1 expression.…”

“…Recently, dysregulation of AMP-activated protein kinase (AMPKα1) signaling has been implicated in oxidative stress-induced vascular and kidney dysfunction [20][21][22]. Although the effects of miR-137 have been linked to oxidative stress [23], the effects of miR-137 and its precise mechanisms remain incompletely unclear.…”

Chinese medicine for diabetic kidney disease in China

“…Berberine may also protect the kidney from injury by modulating the EP4‐Gαs‐cAMP signalling pathway . Activation of AMP‐activated protein kinase is largely involved in the renoprotective effects of berberine …”