The transcription factor Twist1 in the distal nephron but not in macrophages propagates aristolochic acid nephropathy

Aristolochic acid nephropathy (AAN) is a rapidly progressive renal disease caused by the ingestion of plant products containing aristolochic acid (AA), first described in connection with the use of Chinese herbal medicines. Although the true worldwide extent of this disease is unknown, it is likely to represent a significant cause of chronic kidney disease (CKD) in many parts of the world. Furthermore, recent data have also demonstrated that AA is also the primary aetiological agent in Balkan endemic nephropathy. AAN is notable in its association with urothelial malignancy, with the mechanisms of carcinogenesis now well characterized. Aside from a possible role for corticosteroid therapy in slowing disease progression in selected patients, no disease-specific treatments have yet been shown to alter the course of this nephropathy. Therefore, prevention of exposure to AA and, in affected patients, effective management of the risk of malignancy are key principles in the approach to this condition. Although preparations containing Aristolochia spp. and herbs that can be confused or substituted for Aristolochia have been banned in many countries, other herbal products containing AA have continued to be available to consumers long after these bans have been instituted, highlighting the ongoing need for awareness of this disease.

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Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa215 ◽

2020 ◽

Author(s):

Verena Klämbt ◽

Max Werth ◽

Ana C Onuchic-Whitford ◽

Maike Getwan ◽

Thomas M Kitzler ◽

...

Keyword(s):

Transcription Factor ◽

Transcriptional Activity ◽

Kidney Development ◽

Renal Tubules ◽

Loss Of Function ◽

Distal Nephron ◽

Truncating Mutation ◽

Whole Exome ◽

Hypokalemic Alkalosis ◽

Echogenic Kidneys

Abstract Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

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