Chronic kidney disease (CKD) is quite common and often leads to end-stage renal disease (ESRD) with the resultant need for renal replacement therapy. Micro-albuminuria, proteinuria, hyper-filtration, and impaired renal function occur with obesity, suggesting that excess renal lipids, particularly free fatty acids (FFAs), may directly injure and/or indirectly damage the kidneys via increased oxidative stress and inflammation. An excess of renal lipids can damage renal tubule cells. Immune inflammatory pathways can induce oxidative stress, resulting in podocyte injury and protein deposition in the extracellular matrix of the nephron. Using two different murine models of renal disease associated with obesity, we have discovered that retinoic acid receptor ?2 (RAR?2) agonists protect kidneys against lipotoxicity. RAR?2 is a member of a family of nuclear transcription factors that are activated by retinoids (derivatives and metabolites of vitamin A (retinol). We hypothesize that renal lipid accumulation is a key contributor to dysfunction in both the glomerular and tubular compartments and that this excess renal lipid accumulation can be prevented or reversed through the use of highly selective agonists of RAR?2. A corollary to this hypothesis is that renal dysfunction may be reversed by this RAR?2 agonist. We will test this hypothesis in three aims:
in Specific Aim (1), we will test (in pre-clinical drug efficacy studies) selective RAR?2 agonists (AC261066, AC55649) to determine if these synthetic retinoids can (a) decrease the lipid deposition in the kidneys and (b) improve or stabilize kidney function in obesity-induced chronic kidney disease, indicating that these drugs could potentially be used to treat human patients who present with CKD associated with obesity. We will use two murine models, a high fat diet (HFD)-induced obesity model and db/db mice, a genetic model of obesity-associated CKD.
In Specific Aim (2), we will explore the molecular mechanism(s) by which RAR?2 agonists reduce lipid accumulation and renal inflammation in these mouse models.
Aim (2) will also test whether the RAR?2 agonists are acting via RAR?2 expressed in particular types of cells in the kidney through the use of renal cell type specific RAR? knockout mice.
In Specific Aim (3), we will use cell culture models to ascertain if RAR?2 agonists act on podocytes, mesangial cells, and/ or proximal tubule cells via the RAR?2 receptor. Selective RAR?2 agonists have not been tested for treatment of obesity-induced CKD. Thus, our proposed research may define a specific, novel drug target and identify new drugs that treat, and even prevent obesity- associated nephropathy or, possibly, other types of CKD. The strengths of our application include our published work showing that the RAR?2 agonists inhibit the development of renal and hepatic steatosis in genetic and dietary obesity-induced murine disease models; the unique reagents in our possession, such as the conditional knockout RAR? mice; and our research team at Weill Cornell that includes researchers with considerable experience in retinoid pharmacology, mouse models, and renal histology and pathology.
We anticipate that retinoic acid receptor (RAR) ? agonists will be successful in diminishing the severity of nephropathy in a mouse model of obesity by diminishing both the steatosis and inflammation induced in the kidney concomitant with kidney injury. Data from this study could lead to new molecular targets for treatment of various kidney disorders.
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|Marino, Alice; Sakamoto, Takuya; Tang, Xiao-Han et al. (2018) A Retinoic Acid ?2-Receptor Agonist Exerts Cardioprotective Effects. J Pharmacol Exp Ther 366:314-321|