Chronic lithium treatment induces novel patterns of pendrin localization and expression

Abstract

Prolonged lithium treatment is associated with various renal side effects and is known to induce inner medullary collecting duct (IMCD) remodeling. In animals treated with lithium, the fraction of intercalated cells (ICs), which are responsible for acid-base homeostasis, increases compared with renal principal cells (PCs). To investigate the intricacies of lithium-induced IMCD remodeling, male Sprague-Dawley rats were fed a lithium-enriched diet for 0,1, 2, 3, 6, 9, or 12 wk. Urine osmolality was decreased at 1 wk, and from 2 to 12 wk, animals were severely polyuric. After 6 wk of lithium treatment, approximately one-quarter of the cells in the initial IMCD expressed vacuolar H-ATPase, an IC marker. These cells were localized in portions of the inner medulla, where ICs are not normally found. Pendrin, a Cl/[Formula: see text] exchanger, is normally expressed only in two IC subtypes found in the convoluted tubule, the cortical collecting duct, and the connecting tubule. At 6 wk of lithium treatment, we observed various patterns of pendrin localization and expression in the rat IMCD, including a novel phenotype wherein pendrin was coexpressed with aquaporin-4. These observations collectively suggest that renal IMCD cell plasticity may play an important role in lithium-induced IMCD remodeling.

Absence of E-Cadherin and β-Catenin in the Basal Plasma Membrane of Collecting Duct Cells During NDI Development and Recovery

“…9 This is supported by observations of novel cell types in the CD displaying both intercalated and principal cell markers after Li-treatment and recovery. 10,42 In addition, both Type A and Type B intercalated cells have previously been demonstrated to be derived from AQP2-positive cells in the developing kidney. 43 The loss of basal labeling and cellular detachment could potentially occur during a transition from one cell type to another.…”

Low exposition to lithium prevents nephrogenic diabetes insipidus but not microcystic dilations of the collecting ducts in long‐term rat model

“…Long‐term exposure to lithium has been demonstrated to induce remodeling of the CDs, particularly in the inner medulla, characterized by the presence of pendrin‐positive cells. [ 27 ] Therefore, we assessed pendrin expression across various renal segments to determine whether low‐dose exposure altered its expression pattern. Consistent with prior findings, we observed that pendrin expression was markedly higher in the cortex compared to the deepest segments, by at least a five‐fold increase [ 28 ] (Figure 4).…”

“…Interestingly, there were no significant variations observed within each segment between control and lithium‐treated rats, in contrast to the findings reported by Himmel et al, who administered a high dose of lithium. [ 27 ]…”

“…Long-term exposure to lithium has been demonstrated to induce remodeling of the CDs, particularly in the inner medulla, characterized by the presence of pendrin-positive cells. [27] Therefore, we assessed pendrin expression across various renal segments to determine whether low-dose exposure altered its expression pattern.…”

The pathophysiology of distal renal tubular acidosis

“…Kidney biopsy samples from patients receiving lithium show diffuse tubulointerstitial nephritis 134 but whether this inflammation could cause dRTA is unclear and no studies have specifically examined intercalated cells. In a rat model of chronic lithium ingestion, increased pendrin expression and aberrant pendrin localization were observed in the inner medulla 135 . Hypothetically, increased pendrin activity could mediate inappropriate bicarbonate secretion into urine, resulting in renal acidosis similar to that seen in a mouse model of pseudohypoldosteronism type II (PHAII) with elevated pendrin activity 136 .…”