Podocytes play an important role in maintaining the structural integrity of glomerular capillaries. There is a limited capacity of podocytes to reproduce; therefore, they are required to support a greater capillary surface area in states of glomerular hypertrophy (i.e., reduced podocyte density). Such reductions in podocyte density can lead to podocyte dysfunction and is thought to substantially increase the susceptibility to hypertension-induced renal injury and progression of chronic kidney disease. However, the extent to which reduced podocyte density increases the susceptibility to hypertension-induced renal injury remains unknown. The goal of this study was to determine the susceptibility to hypertension-induced renal injury in a rodent model of chronic kidney disease with podocyte dysfunction. Male Sprague-Dawley rats were subjected to normotensive renal mass reduction and instrumented with a radiotelemeter for the continuous measurement of blood pressure. After a two week recovery from surgery to allow for completion of renal compensatory increases in size and function, groups of rats were administered a single dose of puromycin aminonucleoside (PAN, 75 mg/kg i.p.), which acutely injures podocytes, or saline (sham). Rats were followed for 4 weeks following PAN or saline injection. At one week post PAN injection, some groups of rats were administered antihypertensive regimens consisting of hydralazine (50-300 mg/L) + hydrochlorothiazide (HCTZ, 25-75 mg/L) or enalapril (50-300 mg/L) + HCTZ (25-75 mg/L) via the drinking water for the remainder of the study. At the end of the study, glomerulosclerosis (GS) was assessed in a blinded fashion and podocyte density was determined using immunofluorescence detection of the podocyte marker Wilms Tumor 1 (WT1) on paraffin-embedded sections from perfused-fixed kidneys. No differences were observed between antihypertensive groups, thus these data are presented as a singled group. The average systolic BP (mmHg) was higher (P<0.05) in rats administered PAN (144±3, n=12) vs. PAN + antihypertensives (127±2, n=20) and saline (130±4, n=17). The magnitude of glomerulosclerosis (GS, % glomeruli exhibiting GS in 100 evaluated) was greater (P<0.05) in rats administered PAN (64±7%) vs. PAN + antihypertensives (30±6%) vs. saline (6±2%). The slope of the relationship between BP and GS (Δ%GS vs. ΔmmHg) was significantly greater (P<0.05) in rats administered PAN (1.1) and PAN + antihypertensives (1.2) vs. saline (0.4). Podocyte density (podocytes/µm3x10-6) was assessed in non-injured glomeruli from a subset of rats from each group and was significantly greater (P<0.05) in those administered PAN + antihypertensives (63±3, n=8) and tended to be greater (P=0.09) in those administered saline (56±4, n=7) as compared to those administered PAN (47±4, n=7). The number of podocytes per glomerular tuft tended to be lower and the average glomerular tuft area tended to be higher in rats administered PAN vs. the other groups; however, these differences were not statistically significant. These data demonstrate that acute podocyte dysfunction increases the susceptibility to BP-induced GS by ~ 3-fold and that lowering BP in such states mitigates further reductions in podocyte density and progression of kidney disease.