A DUAL COX‐2/sEH INHIBITOR TREATED KIDNEY INJURY IN A DRUG‐INDUCED GLOMERULAR DISEASE MODEL
Authors: Jankiewicz Wojciech K. , Khan Md Abdul H. , Stavniichuk Anna , Vogel Amy , Savchuk Olexiy , Hwang Sung H. , Hammock Bruce D. , Imig John D. 
Published: April 2020

Glomerular diseases are a significant clinical concern: they affect large numbers of patients and we lack effective pharmacological treatment options. Here, we set out to investigate dual cyclooxygenase (COX‐2) / soluble epoxide hydrolase (sEH) inhibition with PTUPB in a model of glomerular disease as a strategy for treating glomerular injury. To model glomerular injury, we used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. Male Sprague Dawley rats were given a high‐salt diet (8% NaCl) and administered a common VEGF inhibitor, sorafenib, over the course of 8 weeks. The study included three experimental groups; (1) healthy control group comprised of untreated rats (n=4–8), (2) vehicle group of rats treated with a VEGF inhibitor, sorafenib (20mg/kg/d p.o.; n=4–8), and (3) PTUPB‐treated group consisting of rats which were initially treated only with sorafenib for 4 weeks and subsequently co‐administered PTUPB (10mg/kg/d i.p.; n=4–8) from weeks 4 to 8. Blood pressure was measured every two weeks. After 4 weeks, sorafenib‐treated rats developed hypertension (177±9 mmHg), in contrast to vehicle rats (135±7 mmHg), and sorafenib resulted in a further elevation in blood pressure on week 8 (205±10 mmHg). PTUPB treatment attenuated the sorafenib‐induced blood pressure elevation and blood pressure remained at 173±12 mmHg on week 8. Urine was collected every two weeks for biochemical analysis. After 4 weeks, sorafenib rats developed pronounced proteinuria (9.0±2 protein/creatinine), which intensified significantly (32.0±4 protein/creatinine) by the end of week 8 compared to control (2.4±0.8 protein/creatinine). PTUPB mitigated sorafenib‐induced proteinuria and by week 8 PTUPB reduced proteinuria to 75% of that in vehicle sorafenib group. Plasma and kidney tissue were collected at the end of the 8‐week protocol. Terminal kidney histopathology revealed tubular cast formation, glomerular injury, and glomerular nephrin loss in sorafenib rats compared to healthy control rats. PTUPB treatment reduced (i) renal structural injury, (ii) tubular cast formation, and (iii) glomerular injury by 30 to 70% compared to sorafenib vehicle group as well as restored (iv) glomerular nephrin expression levels. Sorafenib caused renal oxidative stress as indicated by higher kidney malondialdehyde content (32.0±4g/mg protein) and lower renal tissue nitric oxide level (NO3/NO2 ratio: 0.60±0.07 μmol/μmol) compared to healthy control rats. Consistent with renoprotective action, PTUPB reduced sorafenib‐induced renal oxidative stress as indicated by 26% lower MDA content and a two‐fold higher kidney NO3/NO2 ratio compared to sorafenib vehicle group. Our data demonstrate that PTUPB produced an antioxidant effect in the kidney and mitigated progression of glomerular disease.

Support or Funding Information

DK103616 and Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A. to John D. Imig