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Journal of Clinical Medicine Sep 2023Sjögren's syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS... (Review)
Review
Current Views on Pathophysiology and Potential Therapeutic Targets in Sjögren's Syndrome: A Review from the Perspective of Viral Infections, Toll-like Receptors, and Long-Noncoding RNAs.
Sjögren's syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.
PubMed: 37762814
DOI: 10.3390/jcm12185873 -
Endocrine Journal Jul 2023Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have... (Review)
Review
Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl and HCO3 levels showed significant correlations with K levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.
Topics: Adult; Humans; Child; Adolescent; Pseudohypoaldosteronism; Hypoaldosteronism; Acidosis; Mutation; Hyperkalemia
PubMed: 37081692
DOI: 10.1507/endocrj.EJ22-0607 -
Cell Communication and Signaling : CCS Feb 2024Tubulointerstitial kidney disease associated microenvironmental dysregulation, like acidification, inflammation and fibrosis, affects tubule cells and fibroblasts....
BACKGROUND
Tubulointerstitial kidney disease associated microenvironmental dysregulation, like acidification, inflammation and fibrosis, affects tubule cells and fibroblasts. Micromilieu homeostasis influences intracellular signaling and intercellular crosstalk. Cell-cell communication in turn modulates the interstitial microenvironment. We assessed the impact of acidosis on inflammatory and fibrotic responses in proximal tubule cells and fibroblasts as a function of cellular crosstalk. Furthermore, cellular signaling pathways involved were identified.
METHODS
HK-2 (human proximal tubule) and CCD-1092Sk (human fibroblasts), in mono and coculture, were exposed to acidic or control media for 3 or 48 h. Protein expression of inflammation markers (TNF, TGF-ß and COX-2), dedifferentiation markers (N-cadherin, vinculin, ß-catenin and vimentin), fibrosis markers (collagen III and fibronectin) and phospho- as well as total MAPK levels were determined by western blot. Secreted collagen III and fibronectin were measured by ELISA. The impact of MAPK activation was assessed by pharmacological intervention. In addition, necrosis, apoptosis and epithelial permeability were determined.
RESULTS
Independent of culture conditions, acidosis caused a decrease of COX-2, vimentin and fibronectin expression in proximal tubule cells. Only in monoculture, ß-Catenin expression decreased and collagen III expression increased in tubule cells during acidosis. By contrast, in coculture collagen III protein expression of tubule cells was reduced. In fibroblasts acidosis led to an increase of TNF, COX-2, vimentin, vinculin, N-cadherin protein expression and a decrease of TGF-ß expression exclusively in coculture. In monoculture, expression of COX-2 and fibronectin was reduced. Collagen III expression of fibroblasts was reduced by acidosis independent of culture conditions. In coculture, acidosis enhanced phosphorylation of ERK1/2, JNK1/2 and p38 transiently in proximal tubule cells. In fibroblasts, acidosis enhanced phosphorylation of p38 in a sustained and very strong manner. ERK1/2 and JNK1/2 were not affected in fibroblasts. Inhibition of JNK1/2 and p38 under coculture conditions reduced acidosis-induced changes in fibroblasts significantly.
CONCLUSIONS
Our data show that the crosstalk between proximal tubule cells and fibroblasts is crucial for acidosis-induced dedifferentiation of fibroblasts into an inflammatory phenotype. This dedifferentiation is at least in part mediated by p38 and JNK1/2. Thus, cell-cell communication is essential for the pathophysiological impact of tubulointerstitial acidosis.
Topics: Humans; Acidosis; Cadherins; Catenins; Collagen; Cyclooxygenase 2; Fibroblasts; Fibronectins; Fibrosis; Inflammation; p38 Mitogen-Activated Protein Kinases; Vimentin; Vinculin; Mitogen-Activated Protein Kinase 14
PubMed: 38395872
DOI: 10.1186/s12964-024-01527-8 -
BMC Nephrology Aug 2023Renal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren's syndrome. Renal tubular... (Review)
Review
BACKGROUND
Renal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren's syndrome. Renal tubular dysfunction due to interstitial nephritis has been considered the underlying pathophysiology connecting renal tubular acidosis and primary Sjögren's syndrome. However, the detailed mechanisms underlying the pathophysiology of renal tubular acidosis in primary Sjögren's syndrome is not fully understood.
CASE PRESENTATION
A 30-year-old woman was admitted with complaints of weakness in the extremities. The patient was hospitalized thirteen years earlier for similar issues and was diagnosed with hypokalemic paralysis due to distal renal tubular acidosis with primary Sjögren's syndrome. This diagnosis was based on a positive Schirmer's test. Besides, anti-Sjögren's syndrome-related antigen A was also detected. Laboratory tests indicated distal RTA; however, a renal biopsy showed no obvious interstitial nephritis. Laboratory tests conducted during the second admission indicated distal renal tubular acidosis. Therefore, a renal biopsy was performed again, which revealed interstitial nephritis. Histological analysis of acid-base transporters revealed the absence of vacuolar type H-ATPases in the collecting duct. The vacuolar type H-ATPase was also absent in the past renal biopsy, suggesting that the alteration in acid-base transporters is independent of interstitial nephritis.
CONCLUSIONS
This case study demonstrates that vacuolar-type H-ATPases are associated with distal renal tubular acidosis, and distal renal tubular acidosis precedes interstitial nephritis in patients with primary Sjögren's syndrome.
Topics: Female; Humans; Adult; Acidosis, Renal Tubular; Nephritis, Interstitial; Sjogren's Syndrome; Paralysis; Hypokalemia; Membrane Transport Proteins; Vacuolar Proton-Translocating ATPases; Antibodies
PubMed: 37582721
DOI: 10.1186/s12882-023-03290-3 -
Renal Failure Dec 2024Renal involvement of primary biliary cholangitis (PBC) usually presents as distal renal tubular acidosis. Proximal tubular (PT) dysfunctions in PBC were rarely reported...
INTRODUCTION
Renal involvement of primary biliary cholangitis (PBC) usually presents as distal renal tubular acidosis. Proximal tubular (PT) dysfunctions in PBC were rarely reported with unclear clinicopathological characteristics and renal prognosis.
METHODS
We identified 11 cases of PBC with PT dysfunctions (PBC-PT). Their medical document, kidney pathology, and follow-up data were retrospectively reviewed and analyzed.
RESULTS
The 11 PBC-PT patients were mainly middle-aged (57.8 ± 5.2 years) females (81.8%). Most of them were asymptomatic PBC (7, 63.6%) with a high prevalence of elevated serum immunoglobulin M (IgM, 81.8%) and G (IgG, 54.5%) levels. In the kidney, they had a mean estimated glomerular filtration rate (eGFR) level of 46.54 ± 23.03 ml/min/1.73m, and 81.8% of them had eGFR below 60 ml/min/1.73m. They showed different degrees of PT dysfunctions, including hyperuricosuria, hypouricemia, normoglycemic glycosuria, generalized aminoaciduria, hyperphosphaturia, and hypophosphatemia. Their kidney pathology showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates, brush border defects, and proximal tubulitis. After glucocorticoids treatment, the PT dysfunctions manifesting as hypophosphatemia, hypouricemia, and renal glycosuria all recovered, and the eGFR levels were improved from 43.24 ± 19.60 ml/min/1.73m to 55.02 ± 21.14 ml/min/1.73m ( = 0.028), accompanied by significant improvements of serum IgM levels (from 5.97 ± 4.55 g/L to 2.09 ± 1.48 g/L, = 0.019).
CONCLUSIONS
The PT dysfunctions were rare in PBC patients, and glucocorticoids treatment could benefit the improvements of eGFR and tubular functions.
Topics: Middle Aged; Female; Humans; Retrospective Studies; Liver Cirrhosis, Biliary; Nephritis, Interstitial; Immunoglobulin M; Hypophosphatemia
PubMed: 38275162
DOI: 10.1080/0886022X.2024.2302409 -
Journal of the American Society of... May 2024Foxp1 is a key transcriptional factor for the differentiation of intercalated cells in collecting ducts. Dmrt2 and Hmx2 act downstream of Foxp1 to control the...
KEY POINTS
Foxp1 is a key transcriptional factor for the differentiation of intercalated cells in collecting ducts. Dmrt2 and Hmx2 act downstream of Foxp1 to control the differentiation of type A and type B intercalated cells, respectively. Foxp1 and Dmrt2 are essential for body acid–base balance regulation.
BACKGROUND
Kidney collecting ducts comprise principal cells and intercalated cells, with intercalated cells playing a crucial role in kidney acid–base regulation through H and HCO secretion. Despite its significance, the molecular mechanisms controlling intercalated cell development remain incompletely understood.
METHODS
To investigate the specific role of Foxp1 in kidney tubular system, we specifically deleted expression in kidney distal nephrons and collecting ducts. We examined the effects of on intercalated cell differentiation and urine acidification. RNA sequencing and Chip-seq were used to identify Foxp1 target genes. To dissect the genetic network that regulates intercalated cell differentiation, -deficient mice were generated to determine the role of Dmrt2 in intercalated cell differentiation. -deficient mice were crossed with -deficient mice to dissect the relation between Foxp1 and Notch signaling.
RESULTS
Foxp1 was selectively expressed in intercalated cells in collecting ducts. The absence of Foxp1 in kidney tubules led to the abolishment of intercalated cell differentiation in the collecting ducts, resulting in distal renal tubular acidosis. Foxp1 regulates the expression of and , two genes encoding transcription factors specifically expressed in type A and type B intercalated cell cells, respectively. Further genetic analysis revealed that Dmrt2 was essential for type A intercalated cell differentiation, and Foxp1 was necessary downstream of Notch for the regulation of intercalated cell differentiation.
CONCLUSIONS
Foxp1 is required for the renal intercalated cell differentiation and participated in acid–base regulation. Foxp1 regulated downstream transcriptional factors, Dmrt2 and Hmx2, which were involved in the specification of distinct subsets of intercalated cells.
Topics: Animals; Cell Differentiation; Forkhead Transcription Factors; Mice; Acid-Base Equilibrium; Repressor Proteins; Kidney
PubMed: 38332484
DOI: 10.1681/ASN.0000000000000319 -
Indian Pediatrics Dec 2023We report clinical and etiological profile of 19 children (10 males) with renal rickets managed in the years 2021-2022. Median (IQR) age of presentation was 60 (18-96)...
We report clinical and etiological profile of 19 children (10 males) with renal rickets managed in the years 2021-2022. Median (IQR) age of presentation was 60 (18-96) months. The commonest cause was renal tubular acidosis (n=8). Genetic analysis revealed the diagnosis in 83% subjects (5 out of 6 tested).
Topics: Male; Child; Humans; Child, Preschool; Rickets; Chronic Kidney Disease-Mineral and Bone Disorder; Acidosis, Renal Tubular
PubMed: 38087789
DOI: No ID Found -
World Journal of Diabetes Jul 2023Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for... (Review)
Review
Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.
PubMed: 37547592
DOI: 10.4239/wjd.v14.i7.1049