Experimental Biology 2020 Meeting Abstracts.

Abstract

Bone morphogenetic proteins (BMPs) are growth factors that belong to the transforming growth factor-β (TGF-β) superfamily, and till date 15 BMPs have been described. BMPs, first described for their role in bone and cartilage formation, also play a role in renal fibrosis in chronic kidney disease (CKD). There is evidence to indicate that in rodent models of CKD, administration of recombinant BMP1-3 increases renal fibrosis whereas administration of a BMP1-3-neutralizing antibody or BMP-7 antibody reduces renal fibrosis and preserves renal function. The aim of the present study was to investigate changes in gene expression in the renal cortex obtained from cats with kidney disease or calcium oxalate stone formers (CaOx) at necropsy, to identify BMPs associated with renal dysfunction in cats and potential fibrosis. At time of death the circulating levels of creatinine as well as symmetric dimethyl arginine (SDMA), both markers of kidney decline in cats, were significantly higher in cats with renal disease (n=11) or stone-forming cats (CaOx, n=12) when compared to controls (n=19). Using RNAseq in kidney tissue, we found a modest, but significant, increase in the expression of BMP-1 in cats with kidney disease (2.48 fold) and stone formers (1.72 fold), compared to controls (both p<0.01). While the increase in BMP-2 in CaOx cats was significant (1.46 fold; p<0.05 vs Con), the increase in cats with kidney disease was not (1.23 fold; NS). BMP2K, a BMP-2 inducible kinase, was significantly increased in both kidney disease (1.43 fold) and CaOX (1.46 fold) (both p<0.05). In contrast, a significant decrease in BMP4 was observed in both groups (<2.2 fold and 1.68 fold in kidney disease and CaOx, respectively; both p<0.001 vs Con). A decrease was also seen in CRIM 1, a protein associated with podocyte filtration function and whose reduction is associated with fibrosis, in both groups. BMP-7, whose potential therapeutic role in treating CKD and reversing fibrosis has been documented, was modestly decreased in both groups (both less than 1.5 fold) compared to controls. Given that there was an increase in all three forms of TGFβ (TGFβ1, TGFβ2, and TGFβ3), a potent initiator of renal fibrosis, in both groups, and a decline in BMP-7, an endogenous inhibitor of TGFβ signaling in fibrosis, compared to controls, our results profile the BMPs potentially associated with renal fibrosis in cats that may contribute to kidney dysfunction. In summary, a nutritional therapy to slow the progression of kidney dysfunction may benefit from the inclusion of dietary ingredients that attenuate renal fibrosis in cats. SUPPORT OR FUNDING INFORMATION: This study was funded by Hill's Pet Nutrition, Inc.