Molecular pathophysiology of renal tubular acidosis

Abstract

Renal tubular acidosis (RTA) is characterized by metabolic acidosis due to renal impaired acid excretion. Hyperchloremic acidosis with normal anion gap and normal or minimally affected glomerular filtration rate defines this disorder. RTA can also present with hypokalemia, medullary nephrocalcinosis and nephrolitiasis, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. In the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of RTA and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding transporter or channel proteins operating along the renal tubule. Review of the molecular basis of hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding cotransporter, exchanger, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. These gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and degradation, or defective assembly of channel subunits. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal salt homeostasis, urinary mineral excretion, and blood pressure regulation in health and disease. The identification of the molecular defects in inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders.

Keywords: Renal tubular acidosis; acid-base homeostasis; gene mutations.; molecular physiology; tubular transport.

Fig. (1)

Schematic model of bicarbonate (HCO₃^-) proximal reabsorption. The intracellular carbonic acid (H₂CO₃^-) dissociates into H⁺ and HCO₃^- in a reaction catalysed by a cytoplasmic carbonic anhydrase (CAII). At the luminal membrane, H⁺ secretion is due to an especific Na⁺ – H⁺ exchanger (NHE-3), while, at the basolateral membrane, the 1 Na⁺ - 3 HCO₃^- cotransporter (NBC-1) is responsible for HCO₃^- transport to the peritubular capilar. The secreted H⁺ reacts with filtered HCO₃^- to form luminal H₂CO₃, which is dissociated into H₂O and CO₂ by the action of membrane-bound carbonic anhydrase (CAIV). The generated CO₂ diffuses back into the cell to complete the HCO₃^- reabsorption cycle.

Fig. (2)

Schematic model of the α-intercalated cell and the H⁺ secretion in cortical collecting tubule. The α-intercalated cell is responsible for H⁺ secretion by a vacuolar H⁺-ATPase (main pump) and also by a H⁺-K⁺-ATPase. The luminal ammonia (NH₃) buffers H⁺ to form nondiffusible ammonium (NH₄⁺) and divalent basic phosphate (HPO₄^-) is converted to the monovalent acid form (H₂PO₄^-) in H⁺ presence. Intracellularly formed HCO₃^- leaves the cell via Cl^- - HCO^{3 -} exchange, facilitated by an anion exchanger (AE1). Cytoplasmic carbonic anhydrase II (CA II) is necessary to secret H⁺.