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Abstract: TH-PO885

Inhibition of MicroRNA-451 Increases Metabolic Acidosis in a Mouse Model of Insulin Resistance and Early Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

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

Metabolic acidosis (MA) is a common complication of diabetic nephropathy (DN) and is associated with an increased risk of end-stage renal failure. MA has major systemic consequences which include protein wasting, inflammation, insulin resistance, worsened hypertension and bone disease. Several studies suggest a renal protective role of microRNA-451 (miR-451) in ameliorating progression of DN. The current study aimed to elucidate the role of miR-451 in the development of MA in a mouse model of insulin resistance.

Methods

Male TALLYHO/Jng mice (insulin resistant and obese) were placed on a high-fat diet (60% kCal) and divided into two treatment groups. Mice received 8 consecutive weekly intraperitoneal injections of locked nucleic acid (LNA) miR-451-inhibitor or LNA-scramble (2 mg/kg bw; n =8/treatment). 24-hr urine was collected at 2-week intervals. Mice were humanely euthanized after 12 weeks and kidneys harvested.

Results

LNA-miR-451-inhibitor reduced renal expression of miR-451 6-fold in inhibitor treated mice (p=0.0002). Masson’s Trichrome revealed inhibition of miR-451 increased collagen deposition by 68% (p=0.007). Blood chemistry revealed higher blood Na+ concentrations (2.4%; p=0.007) and anion gap (165%; p=0.01) in the mice treated with inhibitor versus vehicle control. There was also a strong trend for lower blood TCO2 (12.6%; p=0.06) and HCO3 (13.6%; p=0.06) in inhibitor-treated mice. There were no significant differences in serum K+ and Cl-. Western blotting analysis of cortex homogenates revealed significant increases in aquaporin-2 (52.8%, p=0.03), the sodium bicarbonate cotransporter (NBCe1) (28.3%, p=0.02) and SNAT3 (80.7%, p=0.0008) in inhibitor-treated mice. Additionally, there was a strong trend for an increase in the a-subunit of the epithelial sodium channel (ENaC) (35.5%, p= 0.05) in inhibitor-treated mice.

Conclusion

These findings suggest miR-451 may protect against the development of acidosis in the setting of insulin resistance and early diabetic nephropathy, further supporting its potential use as a therapuetic target for DN. Upregulation of transporters involved in proximal-tubule ammoniagenesis are likely a response to the acidosis.

Funding

  • Other NIH Support