3.3 PTUPB reduces renal injury in type 2 diabetic obese ZSF1 rats
Obese ZSF1 rats demonstrated marked renal injury compared to lean ZSF1 rats. In obese ZSF1 rats, albuminuria was more than 40 fold higher compared to lean ZSF1 rats. Obese ZSF1 rats had 4 to14-fold higher renal cortical and medullary cast area compared to lean ZSF1 rats. Interventional PTUPB treatment markedly reduced kidney injury with albuminuria reduced by 40% and tubular cast formation reduced by 60% compared to vehicle obese ZSF1 rats. Enalapril also attenuated kidney injury and exhibited an equipotent effect as PTUPB in attenuating albuminuria, while it was relatively weaker in attenuating renal tubular cast formation in obese ZSF1 rats (Figure 3A-D).
Obese ZSF1 rats demonstrated marked glomerular injury with a glomerular injury score that was 80% higher than lean ZSF1 rats. Both interventional PTUPB and enalapril treatments equipotently attenuated glomerular injury by 50% in obese ZSF1 rats (Figure 4 A, C). Consistent with marked glomerular injury, the obese ZSF1 rats had 60% lower renal nephrin expression compared to lean ZSF1 rats. PTUPB and enalapril treatments equipotently elevated nephrin expression in the kidney of obese ZSF1 rats (Figure 4 B, D). Experiments in isolated glomeruli demonstrate that angiotensin II markedly elevated glomerular albumin permeability. Interestingly, PTUPB directly protected the glomerular filtration barrier and attenuated angiotensin II-induced increase glomerular albumin permeability. In the presence of PTUPB, angiotensin II-induced glomerular albumin permeability was >50% lower than angiotensin II alone (Figure 4E).
Renal fibrosis was 60% higher in obese ZSF1 rats compared to lean ZSF1 rats. Interventional PTUPB and enalapril treatments demonstrated marked anti-fibrotic actions and equipotently reduced renal collagen deposition in obese ZSF1 rats (Figure 5A-C).
In the present study, marked renal inflammation with elevated urinary MCP-1 excretion and infiltration of renal macrophages was evident in obese ZSF1 rats. Urinary MCP-1 excretion was 80% higher in obese ZSF1 rats and PTUPB reduced urinary MCP-1 excretion by 53%. Enalapril also demonstrated anti-inflammatory action in obese ZSF1 rats and reduced MCP-1 excretion by 28%. In obese ZSF1 rats, elevated chemokine expression was accompanied by marked renal infiltration of immune cells, and obese ZSF1 rat kidneys had 80% higher CD-68 positive immune cells compared to lean ZSF1 rats. PTUPB and enalapril reduced renal infiltration of immune cells in obese ZSF1 rats by 60 and 45%, respectively (Figure 6A-C). Overall, we demonstrated marked renal injury in type 2 diabetic obese ZSF1 rats. PTUPB and enalapril attenuated renal injury. Interestingly, we demonstrated that PTUPB and enalapril acted similarly with PTUPB being superior in reducing renal tubular injury and inflammation.