Aging and chronic high-fat feeding negatively affect kidney size, function, and gene expression in CTRP1-deficient mice

Abstract

C1q/TNF-related protein 1 (CTRP1) is an endocrine factor with metabolic, cardiovascular, and renal functions. We previously showed that aged Ctrp1 knockout (KO) mice fed a control low-fat diet develop renal hypertrophy and dysfunction. Since aging and obesity adversely affects various organ systems, we hypothesized that aging, in combination with obesity induced by chronic high-fat feeding, would further exacerbates renal dysfunction in CTRP1-deficient animals. To test this, we fed wild-type and Ctrp1 KO mice a high-fat diet for eight months or longer. Contrary to our expectation, no differences were observed in blood pressure, heart function, or vascular stiffness between genotypes. Loss of CTRP1, however, resulted in ~2-fold renal enlargement (relative to body weight), ~60% increase in urinary total protein content and elevated pH, and changes in renal gene expression affecting metabolism, signaling, transcription, cell adhesion, solute and metabolite transport, and inflammation. Assessment of glomerular integrity, the extent of podocyte foot process effacement, as well as renal response to water restriction and salt loading did not reveal significant differences between genotypes. Interestingly, blood platelet, white blood cell, neutrophil, lymphocyte, and eosinophil counts were significantly elevated, whereas mean corpuscular volume and hemoglobin were reduced in Ctrp1-KO mice. Cytokine profiling revealed increased circulating levels of CCL17 and TIMP-1 in KO mice. Compared to our previous study, current data suggest that chronic high-fat feeding affects renal phenotypes differently than similarly aged mice fed a control low-fat diet, highlighting a diet-dependent contribution of CTRP1 deficiency to age-related changes in renal structure and function.

CTRP11 contributes modestly to systemic metabolism and energy balance

“…4,5 Within this family, there is a subgroup of 15 proteins referred to as the C1q/ TNF-related proteins (CTRP1-15), 6 which we have initially identified based on shared sequence homology to the insulin-sensitizing hormone, adiponectin. 7,8 Multiple approaches-involving recombinant protein infusion, transgenic overexpression, and knockout mouse modelshave provided critical in vivo evidence for CTRPs in regulating diverse aspects of glucose and lipid metabolism, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] obesity-linked low-grade inflammation, 10,27 as well as other diverse functions in the heart and vasculature, [28][29][30][31][32][33][34] kidney, [35][36][37] muscle and tendon, 38,39 bone, 40 immune system, [41][42][43][44] and the central nervous system. [45][46][47]…”

CTRP13 ablation improves systemic glucose and lipid metabolism

“…CTRPs control various aspects of glucose and lipid metabolism by either directly acting on metabolic tissues (e.g., liver, adipose tissue, skeletal muscle) or indirectly via their modulatory roles on immune cells and inflammation [ 15 , 30 ]. Additional functions of CTRPs have also been established in the cardiovascular system [ [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] ], kidney [ 43 , 44 ], gut [ 45 ], eye [ 46 , 47 ], musculoskeletal system [ [48] , [49] , [50] ], and brain [ [51] , [52] , [53] ].…”

Loss of CTRP10 results in female obesity with preserved metabolic health

“…The use of gain-and loss-offunction mouse models has helped establish CTRP's role in controlling various aspects of sugar and fat metabolism (12,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Additional diverse functions of CTRPs have also been demonstrated in the cardiovascular (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47), renal (48,49), immune (20,50,51), sensory (52,53), gastrointestinal (54), musculoskeletal (55)(56)(57), and the nervous system (58)(59)(60)(61).…”