Vanderbuilt independant studyPBI-4050 Protects against Diabetic Nephropathy in Type II Diabetes Ming-Zhi Zhang, Raymond C. Harris. Medicine, Vanderbilt, Nashville, TN. Background: Extensive kidney fi brosis occurs in several types of chronic kidney diseases such as severe diabetic nephropathy (DN). PBI-4050, a novel fi rst-in-class orally active low molecular weight compound, has been shown to exhibit anti-fi brotic and antiinfl ammatory properties in different in vivo models, including CKD models. Phase II clinical trials are underway to test its effi cacy in patients with CKD and DN. In the present studies, we examined whether PBI-4050 affected the progression of DN in a mouse model of accelerated type II diabetes. Methods: eNOS-/-db/db mice received vehicle (water) or PBI-4050 (200 mg/kg/day) by gavage either from 8 to 20 weeks of age (early treatment) or from 16-24 weeks of age (late treatment). A subset of mice with late treatment was kept until death to achieve a survival curve. Results: Early PBI-4050 treatment ameliorated the fasting hyperglycemia and abnormal glucose tolerance tests seen in vehicle-treated mice. In addition, PBI-4050 led to higher blood insulin levels (20 wks: 5.29 ± 1.10 versus 2.23 ± 0.42 ng/ml, P<0.05. n="4)." early="" pbi-4050="" treatment="" preserved="" kidney="" function,="" indicated="" by="" higher="" glomerular="" fi="" ltration="" rate="" (gfr="" at="" 20="" wks:="" 0.223="" ±="" 0.024="" (n="10)" versus="" 0.132="" ±="" 0.031="" ml/min/mouse="" (n="5),"><0.05) and="" lower="" acr="" (20="" wks:="" 1537="" ±="" 201="" versus="" 2808="" ±="" 541="" μg/mg,=""><0.05. n=9). pbi-4050 had no effect on blood pressure. late pbi-4050 treatment had similar effects on glucose control and prevention of further increases in acr. late pbi-4050 treatment also led to increased longevity, with 7/8 pbi-4050-treated mice alive at 25 weeks of age versus only 2/8 in vehicle-treated mice. both early and late pbi-4050 treatment protected against progression of dn, as indicated by reduced histological glomerular injury and decreased fi brosis and collagen i and collagen iv expression. pbi-4050 inhibited kidney macrophage infi ltration, oxidative stress and tgf--mediated fi brotic signaling pathways but increased autophagy. conclusions: these studies suggest that pbi-4050 attenuates development of dn in type ii diabetes through improvement of glycemic control and inhibition of renal tgf- -mediated fi brotic pathways in association with decreases in macrophage infi ltration and oxidative stress and increases in autophagy. funding: niddk support n="9)." pbi-4050="" had="" no="" effect="" on="" blood="" pressure.="" late="" pbi-4050="" treatment="" had="" similar="" effects="" on="" glucose="" control="" and="" prevention="" of="" further="" increases="" in="" acr.="" late="" pbi-4050="" treatment="" also="" led="" to="" increased="" longevity,="" with="" 7/8="" pbi-4050-treated="" mice="" alive="" at="" 25="" weeks="" of="" age="" versus="" only="" 2/8="" in="" vehicle-treated="" mice.="" both="" early="" and="" late="" pbi-4050="" treatment="" protected="" against="" progression="" of="" dn,="" as="" indicated="" by="" reduced="" histological="" glomerular="" injury="" and="" decreased="" fi="" brosis="" and="" collagen="" i="" and="" collagen="" iv="" expression.="" pbi-4050="" inhibited="" kidney="" macrophage="" infi="" ltration,="" oxidative="" stress="" and="" tgf--mediated="" fi="" brotic="" signaling="" pathways="" but="" increased="" autophagy.="" conclusions:="" these="" studies="" suggest="" that="" pbi-4050="" attenuates="" development="" of="" dn="" in="" type="" ii="" diabetes="" through="" improvement="" of="" glycemic="" control="" and="" inhibition="" of="" renal="" tgf-="" -mediated="" fi="" brotic="" pathways="" in="" association="" with="" decreases="" in="" macrophage="" infi="" ltration="" and="" oxidative="" stress="" and="" increases="" in="" autophagy.="" funding:="" niddk="" support="">