ENaC activity in the collecting ducts of the STZ‐induced type 1 diabetic Dahl SS rats

Abstract

The epithelial sodium channel (ENaC) is expressed in the aldosterone sensitive distal nephron where it performs sodium reabsorption from the lumen. Previous studies indicate that high glucose upregulates ENaC expression and activity in cultured cortical collecting duct cells. However, activity of this channel has never been studied in a rodent models of diabetes. Streptozotocin (STZ) treatment is a widely accepted approach to study type 1 diabetes (T1D). However, while Sprague Dawley rats or other salt‐resistant rodent models develop hyperglycemia and T1D after STZ treatment, they do not develop essential features of diabetic nephropathy (DN). To address this limitation, we induced T1D in the Dahl Salt‐Sensitive (SS) rat, which is a model of salt‐sensitive hypertension. We and others reported that 11–12 weeks of STZ‐induced diabetes is sufficient for the animals to develop hyperglycemia, polyuria, weight loss, microalbuminuria, nephrinuria and display renal histological lesions typical for patients with DN. T1D was induced in 6 week old male SS rats with a single i.p. injection of 75 mg/kg STZ. An insulin pellet was implanted on day 7 after STZ treatment in order to keep blood glucose around 300 mg/dL. At the end of experiments the animals were sacrificed and the kidneys were flushed and collected for analysis. We did not measure any difference in plasma aldosterone levels between STZ‐treated and control animals. However, single channel patch‐clamp analysis of ENaC activity in isolated split‐opened tubules revealed that high blood glucose levels increased channel activity compared to normoglycemic animals (NPo were 1.57±0.20 and 0.59±0.19 in STZ‐treated and control animals, respectively). Western blotting and immunohistochemical analyses revealed greater abundance of beta‐ENaC subunits in the kidney cortex of hyperglycemic rats. We conclude that high blood glucose levels in T1D cause ENaC hyperactivity that can lead to excessive sodium and water reabsorption.Support or Funding InformationSupported by NIH R00HL116603, R01HL056259.