Abstract: SA-PO393

MicroRNA-451 as an Early Predictor of and Protector against Diabetic Nephropathy (DN)

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Fluitt, Maurice, Georgetown University, Washington, District of Columbia, United States
  • Shivapurkar, Narayan, Georgetown University, Washington, District of Columbia, United States
  • Li, Lijun, Georgetown University, Washington, District of Columbia, United States
  • Ecelbarger, Carolyn M., Georgetown University, Washington, District of Columbia, United States
Background

MicroRNAs (MiRs) play a role in affecting transcription of a number of genes involved in DN progression, and are an attractive target as biomarkers and therapeutics. Recent studies report an early elevation in urine exosomal (UE) miR-451 with developing DN, but that overall higher renal expression was relatively protective. The current study aimed to determine whether UE miR-451 is an early predictor of albuminuria and the effect of miR-451 antagonism on DN progression in mice prone to type 2 diabetes.

Methods

Male TALLYHO/Jng mice were divided into 2 treatment groups. Mice received weekly intraperitoneal injections of locked nucleic acid (LNA)-miR-451-inhibitor or LNA-scrambled compound (2mg/kg bw; n = 8/ treatment) for 8 weeks. All mice were fed a high-fat diet (60% kCal). Urine (24-hr) was collected every 2 weeks. Mice were humanely euthanized after 8 weeks and kidneys, livers, abdominal adipose tissue, and pancreas were collected for analysis. UE were prepared by high-speed centrifugation (200,000xg). MiR-451 was quantified by qRT-PCR.

Results

UE miR451 levels were reduced 97% in antagonist-treated mice by week 2. Urine albumin levels at week 8 were positively correlated to UE miR-451 at week 2 showing potential predictive power (r=0.45). MiR-451 antagonist did not significantly affect final body or kidney weights. Fasting blood glucose (18-hr) did increase in in the inhibitor treated group at week 3, but decreased at 6 weeks. Inhibitor treated mice also presented with greater variability in blood glucose, with some mice becoming hypoglycemic at 6 weeks (blood glucose <65 mg/dl). Blood collected at euthanasia was analyzed by iSTAT. Serum sodium was significantly higher (2.4%) in the LNA-inhibitor treated group (when compared to the scramble-treated group). In addition, BUN and base excess (extracellular fluid) were 16% and 67% lower, respectively, in the LNA-inhibitor treated group. No other blood chemistry parameters were significantly different. Masson’s trichrome-stained were scored for collagen deposition and showed an increase in increased glomerular injury and collagen deposition in the LNA-inhibitor treated group (scores 2.00 versus 2.95, p < 0.001).

Conclusion

Overall, we find that miR-451 may hold promise as an early biomarker for DN in mice, and that therapy to enhance renal expression may be beneficial.

Funding

  • Clinical Revenue Support