Low to moderate doses of dietary resistant starch and a renin-angiotensin system inhibitor exhibit nephroprotective effects through similar mechanisms in a preclinical model of diabetes
Authors: Carrillo Claudia , Arriaga Claudia , O'Brien Rachel , Balk Annie , Loeffelholz Frances , Rowling Matthew 
Published: May 2024

The investigative goal of our study was to determine the molecular mechanisms of nephroprotection of a drug-diet intervention for type II diabetes in a pre-clinical model. Our working hypothesis proposed that a combination of moderate doses of dietary resistant starch and a low-dose renin-angiotensin system (RAS) inhibitor would decrease renal biomarkers associated with the progression and complications of type II diabetes through the modulation of the renal renin-angiotensin system. Four weeks old Zucker Diabetic Fatty rats ( fa/fa) ( ZDF, n=48) and Zucker lean rats (n=7) were obtained from Charles River Laboratories and acclimated for one week. ZDF rats were then randomly assigned to one of three diets: AIN-93G diet with 0% resistant starch (RS), which served as the control diet, AIN-93G diet with 5% RS, or AIN-93 with 10% resistant starch, which were adjusted at the expense of cornstarch in the diet composition, for a total of eight weeks. At six weeks old, they were randomly assigned to daily intraperitoneal (IP) injections of either captopril (at a dose of 0.5 g/kg of body weight) in saline water and ascorbic acid solution or placebo solution, which consisted of just the vehicle, until the end of the 8-weeks. Zucker lean rats were assigned to an AIN-93G diet with 0% RS and administered daily IP placebo injections at the same timeline as the ZDF counterparts. Rats were placed in metabolic cages 12 hours before euthanization by exsanguination to collect urine and feces. Samples and tissues were aliquoted and frozen, respectively, until further analyses. Enzyme-linked immunosorbent assays were used to quantify different renal biomarkers in the urine and serum samples (i.e., 25-hydroxy-vitamin D, albumin, creatinine). Protein was extracted from kidney samples for Western Blot analyses. ZDF 10% RS and captopril group (ZDF 10% cap) had a decrease of 62.5% in urinary protein creatinine ratio, 29% of urinary albumin levels, and 18% of 25-hydroxy vitamin D (25D) levels, compared to the diabetic control group (ZDF 0% RS placebo). The ZDF 10% RS cap group also exhibited a 62% increase in serum 25D levels, while the 5% RS and captopril group had an 8.7% increase in 1,25-dihydroxy-vitamin D levels compared to the diabetic control. The ZDF 10% RS cap group also presented a 5.5% increase in relative abundance of nephrin and a decrease of 5.9% and 33.3% in angiotensin II receptor I and aldosterone synthase relative abundance, respectively, compared to the diabetic control group. Our results suggest that a combination of dietary resistant starch and a RAS inhibitor help to protect kidney integrity in type II diabetic rats, evidenced by a decrease of biomarkers in the urine and expression of proteins that play a part in the RAS, and increase in serum biomarkers and expression of glomerular structural proteins. Our work was funded by a USDA-NIFA grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.