High fat diet is protective against kidney injury in hypertensive-diabetic mice, but leads to liver injury

Abstract

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. To test if combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice, hyperglycemia was induced in genetically hypertensive mice (Lin), followed by HFD regimen. For that, 8-week-old male were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive). LinSTZ were fed a 60% kCal HFD for 8 weeks. Lin mice treated with STZ developed polydipsia, became hypertensive and hyperglycemic. HFD induced weight gain, protected against glomerular hypertrophy, scarring, and albuminuria at endpoint compared to regular diet fed LinSTZ. On the other hand, HFD induced steatosis, liver fibrosis, inflammation, and increase in AST/ALT ratio, characteristics of non-alcoholic liver disease. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS-induced CKD, protected against kidney injury, but inducing liver damage. More studies are necessary to understand the kidney protective mechanisms of HFD when superimposed with hypertension and type 1 diabetes.

Sex-dependent effects of Canagliflozin on kidney protection in mice with combined hypertension-type 1 diabetes

“…Hyperglycemia impairs water reabsorption, leading to dehydration. LinSTZ mice had increased water intake compared to control Lin animals (Fig 1C and 1G), while urinating a volume equivalent to their body weight per day (Fig 1D and 1H), as observed previously observed by our research group [24,32]. CANA was able to reverse polydipsia and polyuria in male LinSTZ mice (Fig 1C and 1D), but not in females (Fig 1G and 1H).…”

“…Hyperglycemia is associated with dysregulated lipid metabolism and liver dysfunction [24,45,46]. In our study, we observed an increase in triglyceride (TG) levels in males LinSTZ, while CANA mice had lower levels TG compared to LinSTZ (Fig 4B).…”

“…We have previously shown that LinSTZ mice have increased water intake and urine output [24]. To investigate whether CANA would have an effect in polydipsia and/or polyuria, mice were placed in metabolic cages for 24h, prior to the endpoint.…”

“…Previous studies from our research center have shown that LinSTZ mice develop accelerated nephropathy [22,24]. It is also known that patients presenting concomitant diabetes and hypertension have increased chances to develop diabetic nephropathy and chronic kidney disease [38,39].…”