Prevention of Obesity-Related Kidney Disease with Olmesartan and Empagliflozin in an Adult Zebrafish Model

Background: Obesity is a risk factor for chronic kidney disease (CKD), acting through multiple potential mechanisms. Zebrafish are an attractive model for studying these mechanisms, and diet-induced obesity leads to obesity-related kidney disease (ORKiD) in adult zebrafish. No studies have examined the effects of pharmacologic interventions to prevent the development of ORKiD in this model. Methods: Adult zebrafish were received a normal diet (ND, 0.03 g/day of Gemma Micro 300), an overfeeding diet (OF, 0.15 g/day) or an overfeeding diet with olmesartan (Olm, an angiotensin receptor blocker [ARB]) or empagliflozin (Empa, a sodium-glucose co-transporter 2 inhibitor [SGLT2i]) for 6 weeks. Kidney morphology was assessed by light micrsocopy and immunohistochemistry. Results: Overfeeding resulted in greater body weight and specific growth rate (Figure 1A and B). OF-fed fish developed glomerulomegaly when compared to ND fed fish; olmesartan and empagliflozin prevented these changes (Figure 1C and 2). Glomeruli in OF-fed fish occupied a similar percentage of kidney area, but at a lower glomerular density than the other groups (Figure 1D and E. The size of glomeruli in OF-fed fish was significantly higher at any given glomerular density (Figure 1F). All overfed groups demonstrated decreased pAKT to AKT ratios (Figure 2) compared to ND. Conclusion: Adult zebrafish are an effective model for testing pharmacologic therapies in ORKiD. This is the first evidence that either an ARB or an SGLT2i prevent the development of kidney pathology during the induction of diet-induced obesity. Neither drug improved kidney insulin sensitivity.