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Western diet promotes renal injury, inflammation, and fibrosis in a murine model of Alström syndrome
Author(s) -
Kim Young Chul,
Ganguly Souradipta,
Nespoux Josselin,
Freeman Brent,
Zhang Haiyan,
Brenner David,
Dhar Debanjan,
Vallon Volker
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01760
Subject(s) - fibrosis , endocrinology , renal function , medicine , inflammation , kidney , masson's trichrome stain , biology
Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1 , which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and chronic kidney disease (CKD). Polymorphisms in ALMS1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors. To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight and 0.2% cholesterol). Body weight was 50% higher in foz vs WT mice on NC, and WD enhanced the difference to 64% (P interaction =0.0002, two‐way ANOVA). Kidney weight to body weight ratio was not different between groups. Plasma creatinine was lower in foz vs WT mice independent of diet, potentially indicating glomerular hyperfiltration in foz mice. Renal mRNA expression of injury marker Kim1 was not affected by WD in WT and was not different between foz and WT mice on NC (P=0.9995), but it was 26‐fold higher in foz vs WT mice on WD (P<0.0001). Likewise, other renal injury markers (Ngal mRNA; histology assessment) and renal markers of inflammation (Tnf, Il6, Il10 and Ccl2 mRNA; CD68‐positive cells) and fibrosis (Col1A1, Timp1 and Tgf‐beta mRNA; Masson’s trichrome staining) were similar in both genotypes on NC, but significantly greater in foz vs WT mice fed a WD. Albuminuria was higher in foz vs WT mice on both diets but WD significantly increased the difference (P interaction =0.0019, two‐way ANOVA). A glucose tolerance test performed in foz and WT mice on a WD revealed similar basal blood glucose levels and subsequent blood glucose profiles. These results indicate that a Western diet sensitizes a murine model of Alström syndrome to kidney injury, inflammation and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in ALMS1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on the kidney. Support or Funding Information The authors were supported by NIH grants R01DK112042, R01DK106102 (VV), the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH‐P30DK079337 (VV), the Department of Veterans Affairs (VV), and by an investigator‐initiated research project by Janssen (DB, VV). DD was supported by NIH/CTRI 1KL2TR001444 and the American Liver Foundation (ALF) “Liver Scholar” grants.