Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis

Boadi, Eugenia Awuah; Shin, Samuel; Yeroushalmi, Samuel; Choi, Byung Wook; Li, Peijun; Bandyopadhyay, Bidhan C.

doi:10.3390/ijms22063050

Cited by 13 publications

(30 citation statements)

References 68 publications

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“…By 2020, Khayyat et al 6 also noticed the here depicted disagreement on the TRPC3 expression in the nephron among different working groups, but did not contribute to the morphological understanding, rather focusing on functional aspects. Awuah Boadi et al 34 reported TRPC3 localization in distal tubular cells little later as supported by our immunostaining. Even though, almost no reports exist on TRPC3 and even less on TRPC5 in the distal tubule or its different segments, we reported the distribution in the different three segments for the sake of completeness.…”

Section: Discussionsupporting

confidence: 85%

“…As mentioned above, especially this localization is poorly investigated with respect to TRPC3. In analogy to the function of TRPC3 in the proximal tubule 11 and to the function of TRPV5 in the distal tubule 11,46 , regulation of luminal [Ca 2+ ] could be suggested as a channel's function in this localization 11,34,35 .…”

Section: Discussionmentioning

confidence: 99%

“…Staying with the former, TRPC3 is for instance suggested to be involved in luminal osmosensation and vasopressin-induced aquaporin-2 (AQP-2) translocation in the collecting duct [31][32][33] . In the proximal tubule TRPC3 is believed to have a nephroprotective function with respect to the sequence of hypercalciuria, nephrocalcinosis, and potentially chronic kidney disease [34][35][36] . A pathogenic role in autosomal dominant proteinuric kidney disease (ADPKD) upon TRPP1/2 loss-of-function mutation has also been suggested 11,37 .…”

Section: Introductionmentioning

confidence: 99%

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New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

Diebolt,

Schaudien,

Junker

et al. 2023

Preprint

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Several reports previously investigated Transient Receptor Potential Canonical subfamily channels 3 and 5 (TRPC3/TRPC5) in the kidney. However, most of the conclusions are based on animal samples or cell cultures leaving the door open for human tissue investigations. Moreover, results often disagreed among investigators. Histological description is lacking since most of these studies focused on functional aspects. Nevertheless, the same reports highlighted the potential differing key-roles of TRPC3 or TRPC5 in various renal disorders. Hence, our interest to investigate the localization of TRPC3 and TRPC5 in human kidneys. For this purpose, both healthy mouse and human kidney samples that were originated from tumor nephrectomies have been prepared for immunohistochemical staining using knockout-tested antibodies. Blocking peptides confirmed antibody specificity. A normalized weighted diaminobenzidine (DAB) area score between 0–3 comparable to a pixelwise H-score was established and employed for semiquantitative analysis. Altogether, our results suggest that glomeruli only express little TRPC3 and TRPC5 compared to several segments of the tubular system. Cortical and medullary proximal tubules are strongly stained. Intermediate tubules, however, are only weakly stained. The distal tubule was studied in three different localizations and depending on species and primary antibody, the staining was marked although slightly varying throughout the different localizations. Finally, the collecting duct was independently of primary antibody more stained in human compared to mouse tissue. We provide evidence that TRPC3 and TRPC5 are differently expressed in various localizations in both mouse and human samples. Especially, the TRPC5 distribution profile, we present here is completely new to our knowledge and raises questions, for instance its physiological relevance in the tubular system. We less verify results of previous studies than propose until now undescribed localizations of TRPC3 and TRPC5 in the mouse but especially and of greater interest in the human kidney. We thereby not only support the translational concept of TRPC channels as key players in physiology and pathophysiology of the human kidney but also present new potential targets to functional analysis.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

Diebolt,

Schaudien,

Junker

et al. 2023

Preprint

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“…One of those metabolic conditions, hypercalciuria, is considered to be the most common metabolic risk factor for calcium stone formation [9]. Meanwhile, renal tubular acidosis (RTA), which is characterized as defective renal acid-base imbalance due to the inability to secrete H + -atoms, may promote CaP formation in the RT [11].…”

Section: Introductionmentioning

confidence: 99%

The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation

Gombedza,

Shin,

Sadiua

et al. 2024

IJMS

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In calcium nephrolithiasis (CaNL), most calcium kidney stones are identified as calcium oxalate (CaOx) with variable amounts of calcium phosphate (CaP), where CaP is found as the core component. The nucleation of CaP could be the first step of CaP+CaOx (mixed) stone formation. High urinary supersaturation of CaP due to hypercalciuria and an elevated urine pH have been described as the two main factors in the nucleation of CaP crystals. Our previous in vivo findings (in mice) show that transient receptor potential canonical type 3 (TRPC3)-mediated Ca2+ entry triggers a transepithelial Ca2+ flux to regulate proximal tubular (PT) luminal [Ca2+], and TRPC3-knockout (KO; -/-) mice exhibited moderate hypercalciuria and microcrystal formation at the loop of Henle (LOH). Therefore, we utilized TRPC3 KO mice and exposed them to both hypercalciuric [2% calcium gluconate (CaG) treatment] and alkalineuric conditions [0.08% acetazolamide (ACZ) treatment] to generate a CaNL phenotype. Our results revealed a significant CaP and mixed crystal formation in those treated KO mice (KOT) compared to their WT counterparts (WTT). Importantly, prolonged exposure to CaG and ACZ resulted in a further increase in crystal size for both treated groups (WTT and KOT), but the KOT mice crystal sizes were markedly larger. Moreover, kidney tissue sections of the KOT mice displayed a greater CaP and mixed microcrystal formation than the kidney sections of the WTT group, specifically in the outer and inner medullary and calyceal region; thus, a higher degree of calcifications and mixed calcium lithiasis in the kidneys of the KOT group was displayed. In our effort to find the Ca2+ signaling pathophysiology of PT cells, we found that PT cells from both treated groups (WTT and KOT) elicited a larger Ca2+ entry compared to the WT counterparts because of significant inhibition by the store-operated Ca2+ entry (SOCE) inhibitor, Pyr6. In the presence of both SOCE (Pyr6) and ROCE (receptor-operated Ca2+ entry) inhibitors (Pyr10), Ca2+ entry by WTT cells was moderately inhibited, suggesting that the Ca2+ and pH levels exerted sensitivity changes in response to ROCE and SOCE. An assessment of the gene expression profiles in the PT cells of WTT and KOT mice revealed a safeguarding effect of TRPC3 against detrimental processes (calcification, fibrosis, inflammation, and apoptosis) in the presence of higher pH and hypercalciuric conditions in mice. Together, these findings show that compromise in both the ROCE and SOCE mechanisms in the absence of TRPC3 under hypercalciuric plus higher tubular pH conditions results in higher CaP and mixed crystal formation and that TRPC3 is protective against those adverse effects.

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“…The calcium‐sensing receptor (CaSR) is a G protein‐coupled receptor with seven transmembrane‐spanning domains, that modulate calcium homeostasis in the parathyroid glands and kidneys 10,11 . An increasing number of studies have reported that CaSR is closely linked with bone metabolism by sensing extracellular calcium (Ca 2+ e ) concentration and responding to its change.…”

Section: Introductionmentioning

confidence: 99%

A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR ‐mediated inhibition of osteoclastogenesis

Yang

Zhao

et al. 2022

The FASEB Journal

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Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium‐sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+e) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα‐transgenic (TNFTG) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+ surface, and osteoclast‐related genes expression are decreased in TNFTG mice fed the rescue diet. Besides, TNFTG mice fed the rescue diet were found to exhibit more CaSR+ area and less NFATc1+/TRAP+ area. Furthermore, at normal Ca2+e concentrations, osteoclast precursors (OCPs) from TNFTG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+e, whereas the expression of NF‐κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+e. Taken together, our findings indicate that high Ca2+e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF‐κB/NFATc1 pathway.

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Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis

Cited by 13 publications

References 68 publications

New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation

A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR ‐mediated inhibition of osteoclastogenesis

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