Mammalian urine concentration: a review of renal medullary architecture and membrane transporters

Abstract

Mammalian kidneys play an essential role in balancing internal water and salt concentrations. When water needs to be conserved, the renal medulla produces concentrated urine. Central to this process of urine concentration is an osmotic gradient that increases from the corticomedullary boundary to the inner medullary tip. How this gradient is generated and maintained has been the subject of study since the 1940s. While it is generally accepted that the outer medulla contributes to the gradient by means of an active process involving countercurrent multiplication, the source of the gradient in the inner medulla is unclear. The last two decades have witnessed advances in our understanding of the urine-concentrating mechanism. Details of medullary architecture and permeability properties of the tubules and vessels suggest that the functional and anatomic relationships of these structures may contribute to the osmotic gradient necessary to concentrate urine. Additionally, we are learning more about the membrane transporters involved and their regulatory mechanisms. The role of medullary architecture and membrane transporters in the mammalian urine-concentrating mechanism are the focus of this review.

Keywords: Aquaporins; Kidney; Renal medulla; Urea transporters.

Fig. 1

The direction of urea, NaCl, and H₂O movement in the vasa recta and long-looped nephron according to countercurrent multiplication and the passive mechanism. See text for details.

Fig. 2

Schematic diagram illustrating the rodent renal medullary nephron segments and blood vessels. A: Four types of thin limbs of Henle’s loops exist in the rodent kidney and include the type 1 (short-looped descending thin limb), type 2 (AQP1-positive long-looped descending thin limb or DTL_upper), type 3 (AQP1-negative long-looped descending thin limb or DTL_lower) and type 4 (ascending thin limb). Arrow in the proximal straight segment shows flow direction; asterisk identifies thick ascending limb. B: The renal blood vessels consist of the unbranched descending and ascending vasa recta. Descending vasa recta connect to capillaries that join a network of branching AVR at any level of the medulla. The capillary networks return plasma to the cortex either directly or by way of the ascending vasa recta.

Fig. 3

Diagrammatic coronal section of the rodent kidney and medullary nephron and collecting duct architecture. A: The corticomedullary osmotic gradient increases from the cortex to the tip of the inner medulla (reaching a maximum of 3000 mOsmol kg⁻¹ H₂0 in the rat). OSOM, outer stripe of the outer medulla; ISOM, inner stripe of the outer medulla. The red box represents the area occupied by nephrons and collecting ducts shown in B and C. The medullary architecture of long-loop nephrons (B) and short-loop nephrons (C) is depicted in schematic diagrams alongside collecting duct (CD) clusters. The ISOM consists of two lateral regions (bundle and interbundle) and the upper inner medulla consists of two lateral regions (intercluster and intracluster). Modified from Wei et al. 2015, with permission.

Fig. 4

Immunolocalization of tubules and vessels in the Munich-Wistar medulla. A: Inner stripe of the outer medulla. Bundle regions (two are circled) consist of DVR, unbranched AVR (not shown) and short loop DTLs. Interbundle regions consist of long-loop DTLs, thick ascending limbs, CDs and networks of branching AVR (AVR are not shown). B: Inner medulla (approximately 900 μm below the outer medulla). Intracluster regions (circles) consist of CDs, descending and ascending thin limbs and networks of branching AVR (the latter three are not shown). The intercluster regions (boxes) consist of descending and ascending thin limbs, DVR and AVR (ATLs and AVR are not shown). Scale bars: 100 μm. Modified from Pannabecker 2013, with permission.

Fig. 5

Ultrastructure of interstitial nodal spaces in a transverse ultrathin section from kangaroo rat inner medulla. Interstitial nodal spaces are marked with an X. AVR, fenestrated ascending vasa recta; ATL, ascending thin limb; CD, collecting duct. Section is from midway between the outer medullary-inner medullary boundary and papilla tip. Scale bar, 10 μm. Reproduced from Issaian et al. 2012, with permission.

Fig. 6

Location of major transporters involved in the urine-concentrating mechanism in the vasa recta and long-looped nephron.

Fig. 7

Apical (lumen) and basolateral (interstitium) localization of urea transporters and aquaporins in the inner medullary collecting duct (IMCD) cell.

Fig. 8

Major transporters involved in urine concentration in the thick ascending limb (TAL) cell. Na⁺-K⁺-2 Cl⁻ cotransporter 2 (NKCC2); renal outer medullary K⁺ channel (ROMK); Ca⁺⁺-activated maxi K⁺ channel (Maxi-K⁺); K⁺-Cl⁻ cotransporter 4 (KCC4); Na⁺-K⁺-ATPase (NKA); chloride channel (CLC-K2). See text for details.