Glomerular Mesangial Proliferation is Mitigated by Seh/cox‐2 Dual‐Inhibition

Chronic kidney disease afflicts millions across the globe, with focal segmental glomerulosclerosis (FSGS) being the most prevalent type of renal disorder. FSGS can result in irreparable damage to the kidney, and even death, if untreated. The kidney filters blood via a network of highly vascularized modules called glomeruli, of which each kidney has approximately one million, and those afflicted with FSGS exhibit damage to these filters. Intraglomerular capillaries are supported by a matrix of cells called the mesangium, and it believed that signals triggering mesangial hypertrophy and proliferation may exacerbate damage to the glomerulus in those with FSGS. Epoxyeicosatrienoic acids (EETs) are positive mediators of renal health and function. Conversely, some EET metabolites are intimated to stimulate mesangial proliferation, which is known to damage the glomerulus. EETs are most notably metabolized by soluble epoxide hydrolase (sEH), but they can also be modified by other enzymes such as cyclooxygenase‐2 (COX‐2), and we have developed a novel drug, PTUPB, that serves as a dual sEH/COX‐2 inhibitor. The objective of this research is to determine if either our non‐hydrolyzable 8,9‐EET analog, or PTUPB, reduces angiotensin II‐associated mesangial proliferation by decreasing the formation of potentially deleterious EET metabolites. Our long term goal is to mitigate the damage caused by FSGS through a better understanding of the role of EETs and their metabolites in glomerular function.Methodshuman primary mesangial cells (p4‐p8) were stimulated in serum‐free media with 100nM angiotensin II (+/−) 100nm or 300nM PTUPB, or 100nM angiotensin II (+/−) 300nM or 1000nM 8,9‐EET analog, for 72‐hours, at which point cells were counted and compared to the control values.ResultsThe administration of 300nM PTUPB or 1000nM 8,9‐EET analog decreased angiotensin II‐mediated mesangial proliferation by 56.01% ± 2.5 (p = 0.0172) and 55.25% ± 5.1 (p = 0.0138), respectively, as compared to the relative increase in proliferation caused by 100nM angiotensin II alone.ConclusionThe mesangium is an important structural component of the glomerulus, but it also serves as a more nuanced mediator or communication in the glomerulus as it directly interfaces with the endothelium and epithelial podocytes. Mesangial proliferation is a known destructive force in FSGS and we have identified two drugs that mitigate the proliferative phenotype in human mesangial cells.Support or Funding InformationR01 DK103616‐01 (John D. Imig). Dr. Ralph and Marian Falk Medical Research Trust ‐ Phase II (John D. Imig).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.