Properties of renal tubular epithelial cells and kidney repair

The renal tubule consists of a single layer of epithelial cells and functions as an integrated unit that converts the glomerular filtrate to final urine. The morphologic and physiologic properties of tubular epithelial cells are remarkably different between tubular segments and exhibit distinct fluid and electrolyte transport properties (Fig 3-3). The solute composition of fluid in the Bowman’s space is dramatically modified along the entire length of the tubule by a combination of reabsorption, secretion and metabolic events.

Figure 3-3 Schematic representation of key elements of the renal tubule that mediate water and ion reabsorption. A more detailed view of sodium and water transporters/channels in proximal tubule, thick ascending limb, and outer (OMCD) and inner medullary collecting duct (IMCD) is shown. PCT, proximal convoluted tubule; CTAL, cortical thick ascending limb; MTAL, medullary thick ascending limb; DCT, distal convoluted tubule; CCD, cortical collecting duct; Na/Glucose, sodium-glucose cotransporter; NHE, Na⁺/H⁺ exchanger; NBC, sodium bicarbonate cotransporter; NaK, Na⁺-K⁺-ATPase;

AQP, aquaporin; NKCC2, Na⁺-K⁺-2Cl^- cotransporter; ENaC, epithelial sodium channel; UT-A, urea transporter A. (From Udo Hasler et al. [6])

Renal tubular cells are polarized

Cell polarity is crucial for many aspects of kidney function. Functionally, apical–basal

tubular epithelial cells face the tubular lumen while the basolateral surface forms cell−matrix interactions and face the interstitial fluid compartment; (2) to generate distinct membranes:

apical and basolateral membranes have different selectivity and capacity for transporting ions and other molecules, owing to the distinct expression of ion channels and transporters at the apical and basolateral cell surface. These two functional properties provide the basis for uni-directional vectorial transport of solutes and fluids against steep concentration gradients, which is essential for appropriate reabsorption and secretion by the kidney [7].

Figure 3-4 A model of transcellular and paracellular transport across kidney epithelia.

Tubular cells reabsorb substances present in the tubule lumen via transepithelial transport.

These substances accumulate in the interstitial space that surrounds the kidney tubules from where they are returned to the capillary blood (Fig 3-4). Transepithelial transport occurs via two different routes: the transcellular pathway and the paracellular pathway. Transcellular transport is performed by specialized transporters and channels that are localized at different

transport occurs between neighboring cells and relies on tight junctions, the most apical structure of junctional complexes.

In the kidney, cell polarity is established during early development of the tubular epithelium and also during repair of existing epithelia following injury [7]. Recent genetic and biochemical studies in invertebrates and vertebrates indicate that epithelial junctional complexes, including tight junctions and adherens junctions, play important roles in establishing and maintaining apical-basal polarity [8,9]. This will be discussed in Chapter 2,

“The epithelial junctional complex”.

Renal tubular cells display a low rate of cellular proliferation

As assayed by a variety of methods, such as by monitoring DNA synthesis and examining various proliferation markers, the normal adult kidney displays a very low rate of cell turnover [10,11]. Once the kidney reaches adult size, the proliferation of glomerular and tubular cells dramatically decreases and the proliferation capacity declines further with aging [12]. Only 0.4 - 1% of the total cell pool in adult rat kidney cycle under physiological conditions [13,14] and less than 0.4% of tubular cells cycle in adult human kidney [15].

Most cells have a limited life span, continuously dying or dividing, albeit with a low turnover rate, to maintain functional tissue homeostasis. Tight regulation of cell growth and division of renal tubular cells is essential for the maintenance of cell number and for proper function of the kidney. Furthermore, unlike other organs such as heart and brain, the kidney has the capacity for self-repair following injury. Renal tubule structure and function is restored via the generation of new cells. Abnormal cell growth occurring either

developmentally or following injury contributes to a broad variety of renal diseases. Such events are commonly associated with hypertrophy, where individual cell size is increased [16].

Intrinsic epithelial cells repair the kidney after injury

Tubular injury, induced by ischemic or toxic insult, results in cell loss by either necrosis or apoptosis. Successful repair of the injured renal tubule requires replacement of these cells with new, functional cells that reconstitute normal tubular transport. The origin of these cells was long a source of debate. The isolation of putative adult kidney stem cells [17-19] and the identification of a renal stem cell niche in the renal papillary interstitium [14,20] indicated that kidney stem cells might contribute to epithelial repair after injury. However, other studies indicated that new cells derive from surviving tubular cells [11,13,21,22]. In 2008, Humphreys and coworkers genetically labeled mouse tubular epithelial, but not interstitial, cells with -galactosidase (lacZ) and examined cell proliferation after acute kidney injury (AKI) [23]. This study provided strong evidence that surviving epithelial cells generate new epithelial cells after injury (Fig 3-5). Recent studies further demonstrated that terminally-differentiated epithelia themselves, rather than intra-tubular stem cells, re-express stem-cell markers during injury-induced de-differentiation and repair [24,25].

Figure 3-5 Surviving epithelial cells generate new cells after injury. Two models for renal repair.

After injury, there is loss of labeled epithelial cells and exposed areas are covered by new cells. Repair by unlabeled extra-tubular stem/progenitor cells would result in the dilution of labelled cells (blue) after repair (model 1) whereas repair by intra-tubular-labeled cells would result in nephrons that remain blue after repair (model 2). The latter possibility was experimentally observed. (Modified from Benjamin D. Humphreys et al. [23])

Effects of injury on tubular cells and on their recovery

Acute kidney injury (AKI) is described as a rapid (ranging from hours to weeks) decrease in kidney function, as revealed by increased levels of serum creatinine [26].

One common cause of AKI is ischemia, which induces a generalized or localized impairment of oxygen and nutrient delivery to kidney cells, and impairs waste product removal from these cells. Tubular cells proliferate upon alleviation of the source of ischemia, a process that can last for a few days. Cell proliferation is most apparent in the proximal tubule but also occurs in other tubule segments, including the collecting duct [22,24,27].

As the kidney recovers from acute injury, epithelial cells spread and possibly migrate to cover the exposed basement membrane. This process is associated with cell de-differentiation

and proliferation and is followed by cell differentiation that restores tubule functional integrity [21,28]. Restoration of cell-cell interactions at adherent and tight junctions is crucial for epithelia recovery (Fig 3-6) [29-31].

Figure 3-6 Effects of ischemic injury on tubular cells and their recovery. Ischemia results in the rapid loss of cytoskeletal integrity and cell polarity and is associated with tight junction disruption.

This leads to backleak of tubular filtrate. Loss of cell–cell contacts exposes the basement membrane, flattens cells and results in the accumulation of nonpolarized epithelial cells that mislocate Na⁺-K⁺-ATPase and cell adhesion molecules. Proximal tubular cells lose their brush border and exhibit a hypertrophic phenotype, which leads to cast formation. Recovery of proximal tubular cell function requires the reestablishment of cell polarity, which involves integrin reorganization, Na⁺-K⁺-ATPase basolateral redistribution and the formation of junctional complexes. (From Asif A. Sharfuddin et al.

[31])