Research On The Protective Role Of Tauroursodeoxycholic Acid In Diabetic Nephropathy And Underlying Mechanisms

Background:Diabetic nephropathy(DN)remains the most common cause of chronic kidney disease(CKD)and end stage renal disease(ESRD)in the developed countries.However,the exact pathogenesis of DN has not been yet fully elucidated.As a primary and independent factor,apoptosis plays an important role in the pathogenesis of DN.Furthermore,cell apoptosis is associated with ER stress,which is involved in the pathogenesis of DN.DN therapy becomes a difficult problem for the clinical renal physicians and also becomes a focus for the researchers all the time.Tauroursodeoxycholic acid,an effective inhibitor of ER stress,can modulate ER function both in vitro and in vivo via stabilizing protein conformation,improving the folding capacity of the ER,facilitating the trafficking of mutant proteins and improve the metabolic disorder in obese mice and protect streptozotocin(STZ)-induced diabetic retinopathy rats.Taken together,we assume that TUDCA exerts protective effect on diabetic nephropathy via inhibiting ER stress.Objectives:We observe the protecive effect of TUDCA on renal damage in diabetic mice and further validate the protection of TUDCA on the apoptosis of human podocytes induced by human serum albumin in vitro.We hope to search for a potential therapy for the treatment of DN via exploring the renoprotecive mechanism of TUDCA.Methods:1.The renal injury of diabetic db/db mice and non-diabetic db/m mice were detected.2.TUDCA was administrated to db/db mice via intraperitoneal injection and the effects of TUDCA on renal injury,ER stress signaling pathway and apoptosis in db/db and db/m mice were determined.3.We constructed a progressive diabetic nephropathy mouse model via uninephrectomy operation.The differences of renal injury between uninephrectomy group and sham group were tested.4.After treating unx-db/db mice with TUDCA,the effects of TUDCA on renal injury,ER stress and apoptosis in unx-db/db mice were determined.5.The conditional immortalized human podocyte cell lines were cultured.Human serum albumin induced ER stress and apoptosis in podocytes,which were pretreated with TUDCA.The effects of TUDCA on ER stress signaling pathway and apoptosis in podocytes were determined.Results:1.In comparison to non-diabetic db/m mice,db/db mice had reduced body weight,blood glucose and proteinuria.2.Treating db/db mice with TUDCA decreased blood glucose and proteinuria,improved tubulointerstitial lesions and inhibited ER stress and tubular cell apoptosis.3.Uninephrectomy at early stage had no effect on body weight and blood glucose in db/db mice.However,unx-db/db mice had more prominent proteinuria,hypertrophic kidneys and higher ratio of kidney weight and body weight compared with sham-db/db mice.4.Treating unx-db/db mice with TUDCA decreased blood glucose and proteinuria,attenuated hypertrophic kidneys and glomerulosclerosis and inhibited ER stress and cell apoptosis.5.Pretreating with TUDCA could attenuated human serum albumin induced ER stress and apopotosis in cultured human podocytes.Conclusion:Tauroursodeoxycholic acid could decrease blood glucose and proteinuria,attenuate hypertrophic kidneys and improve glomerulosclerosis and tubulointerstitial lesions in the db/db mice and also alleviated cultured podocytes apoptosis in vitro,which is associated with inhibition of ER stress signaling pathway and ER stress associated apoptosis.Therefore,TUDCA shows potential as a therapeutic target for the novel prevention and treatment of DN.