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.