Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI

Abstract

Lithium treatment for 4 wk caused severe polyuria, dramatic downregulation in aquaporin-2 (AQP-2) expression, and marked decrease in AQP-2 immunoreactivity with the appearance of a large number of cells without AQP-2 labeling in the collecting ducts after lithium treatment. Surprisingly, this was not all due to an increase in AQP-2-negative principal cells, because double immunolabeling revealed that the majority of the AQP-2-negative cells displayed [H+]ATPase labeling, which identified them as intercalated cells. Moreover, multiple [H+]ATPase-labeled cells were adjacent, which was never seen in control rats. Quantitation confirmed a significant decrease in the fraction of collecting duct cells that exhibited detectable AQP-2 labeling compared with control rats: in cortical collecting ducts, 40 ± 3.4 vs. 62 ± 1.8% of controls ( P < 0.05; n = 4) and in inner medullary collecting ducts, 58 ± 1.6 vs. 81 ± 1.3% of controls ( P < 0.05; n = 4). In parallel, a significant increase in the fraction of intercalated ([H+]ATPase-positive) cells was shown. Urine output, whole kidney AQP-2 expression, cellular organization, and the fractions of principal and intercalated cells in cortex and inner medulla returned to control levels after 4 wk on a lithium-free diet following 4 wk on a lithium-containing diet. In conclusion, lithium treatment not only decreased AQP-2 expression, but dramatically and reversibly reduced the fraction of principal cells and altered the cellular organization in collecting ducts. These effects are likely to be important in lithium-induced nephrogenic diabetes insipidus.

Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney

“…5 lithium in the kidney. 6 Better understanding of cell fate determination in the collecting ducts may help to design new strategies to manage undesirable alterations of the cell composition in the collecting ducts in the future.…”

“…5 The ratio of PCs and ICs can be altered by genetic mutations and chemical treatment, such as lithium. 6,7 Although it is still unclear how lithium treatment induces the increase of ICs, the study of Mib1, a regulator of Notch signaling, suggested that Notch signaling confers PC fate and the absence of Notch signaling results in IC fate. 7 Similar Notch role in cell fate choice, between multiciliated versus transporter cell, was also observed in zebrafish pronephros.…”

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

“…Chronic lithium treatment causes a multitude of structural changes within the kidney. For example, despite increased proliferation of principal cells, the proportion of intercalated cells to principal cells increases after 4 weeks of lithium treatment, suggesting that there is a decrease in principal cell viability (9,10). The observed increase in Akt activation could be a survival response by the principal cell to limit apoptosis and the trigger for induced cell proliferation.…”

“…In addition, lithium induces increased expression of important acid-base transporting proteins including the H ϩ -ATPase and the anion exchanger type 1 (AE1) in the collecting duct (8). These changes may be, at least in part, attributable to an increase in the proportion of intercalated cells compared with principal cells (9), which is associated with increased cell proliferation and apoptosis of principal cells (10). Additionally, further ''remodeling'' of the kidney can occur with lithium treatment, including major structural changes such as medullary tubular cysts and tubular atrophy, resulting in tubulointerstitial fibrosis and renal failure (11).…”

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

“…AQP2 mRNA. Presumably as a result of the toxic effect of lithium on principal cells, chronic lithium therapy (Ͼ4 wk in rats) further results in a decreased number of principal cells to the benefit of intercalated cells (39), which also will contribute to a reduced dDAVP-induced cAMP generation in kidneys of rats that had lithium-induced NDI. Recently, cyclo-oxygenase 2 (COX2) expression was suggested to be involved in lithiuminduced NDI (40), but this was debated by others (41).…”