Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats.

Abstract

We have shown previously that inhibition of sEH (soluble epoxide hydrolase) increased EETs (epoxyeicosatrienoic acids) levels and reduced renal injury in diabetic mice and these changes were associated with induction of HO (haem oxygenase)-1. The present study determines whether the inhibition of HO negates the renoprotective effect of sEH inhibition in diabetic SHR (spontaneously hypertensive rats). After 6 weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor t-AUCB {trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid}, treated with the HO inhibitor SnMP (stannous mesoporphyrin), and treated with both inhibitors for 4 more weeks; non-diabetic SHR served as a control group. Induction of diabetes significantly increased renal sEH expression and decreased the renal EETs/DHETEs (dihydroxyeicosatrienoic acid) ratio without affecting HO-1 activity or expression in SHR. Inhibition of sEH with t-AUCB increased the renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR; however, it did not significantly alter systolic blood pressure. Treatment of diabetic SHR with t-AUCB significantly reduced the elevation in urinary albumin and nephrin excretion, whereas co-administration of the HO inhibitor SnMP with t-AUCB prevented these changes. Immunohistochemical analysis revealed elevations in renal fibrosis as indicated by increased renal TGF-β (transforming growth factor β) levels and fibronectin expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with t-AUCB prevented its ability to reduce renal fibrosis in diabetic SHR. In addition, SnMP treatment also prevented t-AUCB-induced decreases in renal macrophage infiltration, IL-17 expression and MCP-1 levels in diabetic SHR. These findings suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.

• Authors: Ahmed A Elmarakby, Jessica Faulkner, Chelsey Pye, Katelyn Rouch, Abdulmohsin Alhashim, Krishna Rao Maddipati, Babak Baban
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 125 Issue 7 Pg. 349-59 (Oct 2013) ISSN: 1470-8736 [Electronic] England
• PMID: 23611540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
• Actins
• Benzoates
• Enzyme Inhibitors
• Membrane Proteins
• Metalloporphyrins
• nephrin
• stannous mesoporphyrin
• Urea
• Creatinine
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• heme oxygenase-2
• Epoxide Hydrolases

Topics

• Actins (metabolism)
• Albuminuria (prevention & control)
• Animals
• Benzoates (antagonists & inhibitors, pharmacology, therapeutic use)
• Blood Pressure (drug effects, physiology)
• Creatinine (urine)
• Diabetes Mellitus, Experimental (drug therapy, enzymology, physiopathology)
• Diabetic Nephropathies (enzymology, metabolism, prevention & control)
• Disease Progression
• Drug Evaluation, Preclinical (methods)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Epoxide Hydrolases (antagonists & inhibitors, metabolism, physiology)
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, metabolism, physiology)
• Heme Oxygenase-1 (antagonists & inhibitors, metabolism, physiology)
• Kidney Cortex (metabolism)
• Male
• Membrane Proteins (urine)
• Metalloporphyrins (pharmacology)
• Rats
• Rats, Inbred SHR
• Urea (analogs & derivatives, antagonists & inhibitors, pharmacology, therapeutic use)