Thick ascending limb of the loop of Henle

Abstract

The thick ascending limb occupies a central anatomic and functional position in human renal physiology, with critical roles in the defense of the extracellular fluid volume, the urinary concentrating mechanism, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and urinary protein composition. The last decade has witnessed tremendous progress in the understanding of the molecular physiology and pathophysiology of this nephron segment. These advances are the subject of this review, with emphasis on particularly recent developments.

Keywords: Na transport; acidosis; calcium receptor; renal physiology; water transport.

Figure 1.

Organization of the nephron, showing both short-looped and long-looped nephrons. See text for details relevant to the thick ascending limb (TAL). Within the cortex, a medullary ray is delineated by a dashed line. Structures are noted as follows: 1, glomerulus; 2, proximal convoluted tubule; 3, proximal straight tubule; 4, descending thin limb; 5, ascending thin limb; 6, TAL; 7, macula densa; 8, distal convoluted tubule; 9, connecting tubule; 10, cortical collecting duct; 11, outer medullary collecting duct; 12, inner medullary collecting duct.

Figure 2.

Transepithelial Na⁺-Cl⁻ transport pathways in the TAL. See text for details. Barttin, Cl⁻ channel subunit; CLC-NKB, human Cl⁻ channel; KCC4, K⁺-Cl⁻ cotransporter-4; Maxi-K, calcium-activated maxi K⁺ channel (also known as the BK channel); NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter-2; ROMK, renal outer medullary K⁺ channel.

Figure 3.

Ultrastructural localization of NKCC2 protein in the TAL and macula densa (MD). (A) Immunoelectron microscopy of NKCC2 in the TAL. NKCC2 labeling is associated with apical plasma membrane (arrows) and small intracellular vesicles (arrowheads) of TAL cells. Both smooth-surfaced cells (left) and rough-surfaced cells (right) are labeled, with greater labeling of intracellular vesicles in smooth-surfaced cells. (B) Immunogold localization of NKCC2 in ions of MD. Abundant NKCC2 labeling is associated with apical plasma membrane (arrows) of MD cells and TAL cells. Inset: overview showing MD cells and TAL cells. Regions indicated by MD are shown at higher power in main panel from adjacent section. Original magnification, ×3500 in B; ×44,000 in B inset. Reprinted from reference , with permission.

Figure 4.

Bicarbonate transport pathways within the TAL. See text for details. NHE3, Na⁺/H⁺ exchanger-3; CA, carbonic anhydrase.

Figure 5.

Ammonium transport pathways within the TAL. See text for details. NH₄⁺, ammonium; NHE4, Na⁺/H⁺ exchanger-4.

Figure 6.

Model for the interaction of ROMK, NKCC2, SORL1, SPAK/OSR1, and CAB39 with uromodulin in the regulation of ion transport in the TAL. CAB39, calcium-binding protein 39; OSR1, oxidative stress–responsive kinase 1; SORL1, sorting protein-related receptor with A-type repeats 1; SPAK, STE20/SPS1-related proline/alanine-rich kinase; Modified from reference , with permission.

Figure 7.

Expression patterns and distribution of uromodulin in normal and diseased kidney. The segmental distribution and staining pattern of uromodulin was compared in normal kidneys (A–G), and in three kidneys with UAKD due to UMOD mutations (H–M). In the normal human kidney, uromodulin is distributed primarily in the TAL segments (A), with a distinct apical membrane reactivity (B). The segmental distribution to the TAL was demonstrated by lack of cross-reactivity with AQP1 (C and D) and codistribution with SR1A on serial sections (E and F). No specific staining was detected when using nonimmune IgG (G). (H–M) The expression and staining pattern for uromodulin was significantly modified in the three kidneys harboring UMOD mutations. Intense staining for uromodulin was detected in a subset of tubule profiles (H and I) that are sometimes enlarged or cystic. The tubule profiles stained for uromodulin are negative for AQP1 (I and J). (K–M) At higher magnification, the staining for uromodulin is intense, diffusely intracellular, and also heterogeneous within tubular cells. AQP1, aquaporin 1; SR1A, serotonin receptor 1A; UAKD, uromodulin-associated kidney disease. Modified from reference , with permission.