Abstract
Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known. To determine if CAII was required for urinary concentration, we studied water handling in CAII-deficient mice. CAII-deficient mice demonstrate polyuria and polydipsia as well as an alkaline urine and bicarbonaturia, consistent with a type III renal tubular acidosis. Natriuresis and hypercalciuria cause polyuria, however, CAII-deficient mice did not have increased urinary sodium nor calcium excretion. Further examination revealed dilute urine in the CAII-deficient mice. Urinary concentration remained reduced in CAII-deficient mice relative to wild-type animals even after water deprivation. The renal expression and localization by light microscopy of NKCC2 and aquaporin-2 was not altered. However, CAII-deficient mice had increased renal AQP1 expression. CAII associates with and increases water flux through aquaporin-1. Water flux through aquaporin-1 in the TDL of the loop of Henle is essential to the concentration of urine, as this is required to generate a concentrated medullary interstitium. We therefore measured cortical and medullary interstitial concentration in wild-type and CAII-deficient mice. Mice lacking CAII had equivalent cortical interstitial osmolarity to wild-type mice: however, they had reduced medullary interstitial osmolarity. We propose therefore that reduced water flux through aquaporin-1 in the TDL in the absence of CAII prevents the generation of a maximally concentrated medullary interstitium. This, in turn, limits urinary concentration in CAII deficient mice.
Highlights
Carbonic anhydrases are a group of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide into carbonic acid, which in solution rapidly dissociates into bicarbonate and a proton
CAIInull mice have more dilute urine than wild-type animals, even after water restriction. This failure to concentrate urine is due to reduced medullary osmolarity, which we suggest is the consequence of reduced water flux through AQP1
In order to asses the potential physiological role of the CAIIAQP1 interaction, we examined water handling in an animal model devoid of Carbonic anhydrase II (CAII)
Summary
Carbonic anhydrases are a group of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide into carbonic acid, which in solution rapidly dissociates into bicarbonate and a proton. CAII is expressed to varying levels along the nephron with the exception of the thin ascending limb (Purkerson and Schwartz, 2007). It is most prominently expressed in intercalated cells of the distal nephron where it facilitates the secretion of protons (Schwartz, 2002), via a physical and functional interaction with the anion exchanger 1 (AE1). This interaction has been dubbed a transport metabolon (Vince and Reithmeier, 1998, 2000). In the proximal tubule CAII likely participates in sodium reabsorption from the filtrate by binding to apically expressed NHE3 and the basolaterally expressed NBCe1, increasing their activity via the provision of substrate (Becker and Deitmer, 2007; Krishnan et al, 2015)
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