The juxtaglomerular apparatus in Bartter's syndrome and related tubulopathies

Abstract

A comparative immunocytochemical and electron microscopic study was performed on renal biopsies from two children with classical Bartter's syndrome (BS) and three children with a recently described variant, the so-called hyperprostaglandin E-syndrome (HES). Compared to age-matched controls, kidney specimens from patients with BS and HES disclosed a marked hypertrophy and hyperplasia of the juxtaglomerular apparatus (JGA). In addition, in HES focal tubular and interstitial calcifications accompanied by interstitial fibrosis and tubular atrophy were noted. On immunocytochemistry, chronic stimulation of the JGA in BS and HES was characterized by an increase in the number of renin-positive cells, particularly in the media of afferent arterioles, but also in efferent arterioles and in the glomerular stalk. The length of the renin-positive portion of the preglomerular arterioles was significantly increased when compared to controls (100 +/- 32 vs. 49 +/- 17 microns; p less than 0.001). In addition, the immunoreactivity of individual renin-positive cells was markedly enhanced. On electron microscopy, "hypertrophy" of the RER and of Golgi complexes with paracrystalline deposits in dilated RER cisterns and protogranules indicated an increased renin synthesis. Renin could be identified in mature secretory granules as well as protogranules by immune electron microscopy. Angiotensinogen was present in hypertrophied epithelial cells of Bowman's capsule. Converting-enzyme reactivity was observed in controls as well as in BS and HES in the brush border of the proximal tubule. In contrast to previous reports, Angiotensin II was completely negative in control as well as in diseased kidneys. We conclude from our results that both BS and HES are characterized by a marked activation of the JGA and severe stimulation of the renin-angiotensin system. Since activation of this system, however, leads--independently of the primary stimulus--to qualitatively very similar morphological reactions, these results do not implicate a common pathogenetic mechanism to both conditions.

Procollagen I-expressing renin cell precursors

“…They are located in perivascular apposition to afferent arterioles in the juxtaglomerular region (28). Cells in this area are known to express renin upon challenge of the renin-angiotensin system, leading to the visi- ble phenomenon of juxtaglomerular hypertrophy (2,6,22,29). Our findings show that induction of juxtaglomerular hypertrophy is associated with a downregulation of PC1 expression in this area, supporting the idea of an interconversion between renin-expressing and PC1-expressing cells in the normal adult kidney.…”

“…Recruitment of renin-expressing cells in the normal kidney goes along with a parallel induction of renin expression in preglomerular vessel walls and in the juxtaglomerular areas (2,6,22,28,29). It is of note that we found PC1-positive cells in wild-type kidneys selectively in the juxtaglomerular lacis (Goormaghtigh) cell area.…”

Lack of Connexin 40 Causes Displacement of Renin-Producing Cells from Afferent Arterioles to the Extraglomerular Mesangium

“…Endothelial cells of the afferent arterioles, renin-producing cells, and mesangial cells form a network of cells that are connected via Cx40 gap junctions (23-26) ( Figure 6C) and that are derived from the juxta/ periglomerular mesenchyme as a group of pericytes. Notably, all of these cell types, including the extraglomerular and intraglomerular mesangial cells (40,41), have the capability to synthesize renin, although the expression of renin in the adult mesangium is a very rare event (1,(42)(43)(44).…”

“…The inherent capability to produce renin, however, would be preserved. In fact, it is known that long-lasting stimulation of the renin-angiotensin system can lead to the recruitment of renin production not only in the larger vessels but also in the EGM (42)(43)(44)(45)(46)(47).…”

Kidney stone disease

“…Bartter syndromes. Of the 5 major genetic variants associated with Bartter syndrome (49), cortical and medullary renal calcifications (50) are found in patients with Bartter syndrome types I and II (Table 1), which arise from transport defects that reduce thick ascending limb (TAL) NaCl and calcium reabsorption, creating hypercalciuria. Defects in a TAL basolateral membrane chloride channel, CLCNKB, produce only variable hypercalciuria and uncommon crystal deposits (type III).…”