Genetic restoration of aldose reductase to the collecting tubules restores maturation of the urine concentrating mechanism

Abstract

To investigate the underlying causes for aldose reductase deficiency-induced diabetes insipidus, we carried out studies with three genotypic groups of mice. These included wild-type mice, knockout mice, and a newly created bitransgenic line that was homozygous for both the aldose reductase null mutation and an aldose reductase knockin transgene driven by the kidney-specific cadherin promoter to direct transgene expression in the collecting tubule epithelial cells. We found that from early renal developmental stages onward, urine osmolality did not exceed 1,000 mosmol/kgH2O in aldose reductase-deficient mice. The functional defects were correlated with significant renal cellular and structural abnormalities that included cell shrinkage, apoptosis, disorganized tubular and vascular structures, and segmental atrophy. In contrast, the transgenic aldose reductase expression in the bitransgenic mice largely but incompletely rescued urine concentrating capacity and significantly improved renal cell survival, cellular morphology, and renal structures. Together, these results suggest that aldose reductase not only plays important roles in osmoregulation and medullary cell survival but may also be essential for the full maturation of the urine concentrating mechanism.

Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity

“…We used the diuretic furosemide to induce hypo-osmolality in the kidneys of the WT C57BL/6 mice. In addition, we also included a line of knockout mice deficient in AR ( AR - /- , also in C57BL/5 background) that develop mild diabetes insipidus and accumulate hypotonic urine in the medulla due to defects in urine-concentrating mechanisms (26). As a consequence of AR deficiency or diuretics-treatment, the urine osmolarity in the AR -/- mice and the furosemide-treated mice was found to be ∼35 and 17% of that of the age-and gender-matched WT mice, respectively ( P  < 0.001; Figure 6A).…”

“…Wild-type (WT) and AR -deficient ( AR − /− ) male C57BL/6 mice were maintained as described previously (26). Three groups of 6- to 8-week mice were prepared (three per group), i.e.…”

Protective effects of Eucommia lignans against hypertensive renal injury by inhibiting expression of aldose reductase

“…It has been proven that AR was involved in the pathological processes associated with inflammation, ischemia, hypoxia and oxidative stress (Yadav et al, 2010;Ananthakrishnan et al, 2011;Ramana, 2011;Srivastava et al, 2011). Meanwhile, it induced proliferation of mechanocyte and mesangial cells (Che et al, 2005), transition of tubular epithelial cells (Yang et al, 2006;Zablocki et al, 2011) and deposition of extracellular matrix . All of the above elements constituted the basis of hypertensive renal injury.…”

Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

“…Aldose reductase deficient mice ( Akr1b3 −/− ) exhibit a partially defective urine-concentrating ability [3], [4] and renal structural abnormalities [5]. AKR1B1/B3 is also present in a broad range of tissues and other physiological functions based on its enzymatic activities in vitro have been proposed.…”