| Diabetic nephropathy is a common complication of diabetes, an early manifestationof glomerular extracellular matrix proliferation, glomerular filtration and tubular highperfusion. With the progression, the loss of glomerular and tubular cell, leading toglomerulosclerosis and tubular atrophy and interstitial fibrosis. At present，somestudy show that the mechanism of diabetic nephropathy is associated with theautophagy and extracellular matrix deposition.Autophagy is a process of cells self-ea. In nomarl conditions, cells autophagy keeps alow base level, the body may remove a few of damaged intracellular organelles (suchas mitochondria, etc.), and biological macromolecules (e.g., proteins, etc.), cellswere maintained normal physiological function. Some of the current research hasfound that high glucose may inhibit the fuction of autophagy in renal glomerularmesangial cells, so that the cell damage or aging organelles (such as mitochondria)and macromolecules (such as proteins) can not be promptly removed, finally,accumulated in the cells increasing cell damage and aging. While in high glucose,autophagy plays an important role for cell function and glomerular mesangialpodocyte. AMPK/mTOR pathway as an energy target, not only to play an importantrole in regulating glucose and lipid metabolism in liver, fat and skeletal muscle, butalso can adjust the level of autophagy within the kidney, Shao Feng ’s study notedthat in the case of diabetic nephropathy, activating AMPK, inhibiting mTOR,canenhance autophagy activity, reduce oxidative damage, reduce the damage of diabeticnephropathy.What is more, the extracellular matrix (ECM) deposition is closely related to diabeticnephropathy, ECM deposition is mainly due to the unbalance that abnormal synthesisof various components (FN, Col Ⅰ, Col Ⅳ) and degradation. ECM deposition is considered to be an important mechanism causes glomerulosclerosis. It has beenconfirmed that TGF-β1and other cytokines can regulate ECM metabolism. Themechanism may be due to the specific TGF-β1can regulate the synthesis anddegradation of ECM, which can increasing the ECM synthesis, decreasingdegradation. At present studies have shown that activating AMPK can inhibits theexpression of TGF-β1in high glucose condition, and the proliferation of mesangialcells in high glucose. Therefore, the reduction level of autophagy and extracellularmatrix deposition may be related to the pathogenesis of diabetic nephropathy. Butwhether AMPK as promoting autophagy, inhibiting TGF-β1expression, reducing thedeposition of extracellular matrix key target for the treatment of diabetic nephropathyremains to be further argued.2, Huang Gui solid dispersion:Our research group studies confirm berberine can activate AMPK, and with a widerange of pharmacological effects that can reduinge fasting plasma glucose, loweringblood pressure, improving insulin resistance, anti-peroxidation, treating diabetes.Recent studies also show that berberine has various complications of diabetes aremore therapeutic effects, including cardiovascular complications and diabeticnephropathy. But berberine in vivo bioavailability is very low, about5%in the smallintestine, thus limiting the berberine the clinical application of pigment. Sodiumcaprate is a low toxicity and effective absorption enhancers have been used clinicallyas a suppository, is the only approved product can be used in the fatty acid salts ofabsorption enhancers.Our research group desgin that berberine and intestinalabsorption accelerators combination of sodium caprate to increase theirbioavailability, named Huang Gui solid dispersion. However, whether Huang Guisolid dispersion also plays a role in the treatment of diabetic nephropathy as the sameas berberine is unclear. And the mechanism for the regulation of AMPK affectwhether autophagy pathway and inhibiting the activation of extracellular matrixdeposition pathway also to be further explored.Purpose:This paper studies the impact of Huang Gui solid dispersions in type2diabetic rats model, and to explore whether the AMPK is the target of Huang Gui solid dispersionto treat the2diabetic nephropathy and its mechanism of action is through activationof autophagy and inhibition of extracellular matrix the accumulation. while providingthe theoretical basis of clinical treatment of diabetic nephropathy drug selection.Methods and Results:1The protective effection of Huang Gui solid dispersion of diabetic nephropathy rats:The type2diabetes model was induced by high-fat diet and multiple low-doseinjection of STZ, given16weeks Huang Gui solid dispersion treatment,testing bloodglucose, glucose tolerance, rat urine albumin,24-hour urine total protein, serumglucose, creatinine, urea nitrogen; Huang Gui solid dispersion can improve glucosetolerance in diabetic nephropathy rats, reduced fasting serum glucose, creatinine,urea nitrogen,24-hour urine total protein, albumin, elevated urine creatinine, ureanitrogen levels. HE staining showed Huang Gui solid dispersion can significantlycontrol type2diabetic rat glomerular mesangial proliferation, glomerular evenlydistributed yet, glomerular volume decreases after16weeks.2The effection of Huang Gui solid dispersion in diabetic nephropathy rats kidneyabout AMPK expression: detected rats kidney proteins, compared with the modelgroup, Huang Gui solid dispersion can increase the expression of AMPK in thekidney.3The effection of Huang Gui solid dispersion about extracellular matrix depositionand related proteins or pathways: Masson staining showed Huang Gui soliddispersion can be effectively reduced collagen deposition in the kidneys; Huang Guisolid dispersion can be effectively reduced kidney tissue extracellular matrix the maincomponent COL I, COL IV, FN levels, inhibit the accumulation of extracellularmatrix, reduced renal fibrosis. Huang Gui solid dispersion can inhibit the expressionof TGF-β1, while inhibiting the expression of α-SMA, the lower the degree of renalfibrosis.4The effection of Huang Gui solid dispersion in diabetic nephropathy rat kidneyabout autophagy pathway proteins: Huang Gui solid dispersion may increase theexpression of ULK1level in renal of diabetic nephropathy rats, inhibit the expression of mTOR, while increasing the kidney related autophagy protein beclin-1and LC3expression.Conclusion: In summary, Huang Gui solid dispersion diabetic nephropathytherapeutic effect; AMPK may play a protective role in its key target; type2diabeticnephropathy was decreased injury AMPK activation, mTOR pathway extracellularmatrix deposition increases, The mechanism of Huang Gui solid dispersion treatmentof diabetic nephropathy is the increases in AMPK expression, inhibition of mTORsignaling pathway,inhibition of TGF-β1expression, reducing the extracellular matrix(ECM) accumulation. |
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