Null Mutation of PCLN-1/Claudin-16 Results in Bovine Chronic Interstitial Nephritis

Abstract

Inherited chronic renal diseases are associated with failures in glomerular filtration and tubular resorption. Such failures invariably result from defects in selective filtration and absorption in surface renal epithelium. Recently, we described an autosomal recessive chronic interstitial nephritis with diffuse zonal fibrosis (CINF) in cattle. Bovine CINF, characterized by increased blood urea nitrogen, creatinine, and urinary proteins, leads to lethality before puberty, usually within the first 6 months or year of life. Here, we demonstrate that the first four exons of PCLN-1/Claudin-16(CL-16), which encodes a member of the claudin family of tight junction proteins, were deleted in CINF-affected cattle. CL-16was expressed preferentially in kidneys of normal cattle, but transcripts were totally absent in affected offspring. This observation suggests that the lack of CL-16 protein contributes to the dysfunction of paracellular renal transport systems.[The CL-16cDNA sequence has been deposited at GenBank under accession no. AB030082.]

Restricted Localization of Claudin-16 at the Tight Junction in the Thick Ascending Limb of Henle's Loop Together with Claudins 3, 4, and 10 in Bovine Nephrons

“…Interestingly, in contrast to FHHNC, decreases in serum Mg 2+ and Ca 2+ concentrations are not apparent in cattle with claudin-16 deficiency, while a reduction in renal reabsorption rate has been suggested for Mg 2+ [21]. This suggests that there is a compensatory system(s) for metabolism of these divalent cations in the absence of claudin-16 or that bovine claudin-16 may have functions in paracellular transport of Mg 2+ and Ca 2+ distinct from those of the human counterpart despite their high homology in amino acid sequences [9,20].…”

“…Since FHHNC has been characterized by renal Mg 2+ and Ca 2+ wasting, claudin-16 is likely to form aqueous pores that function as the paracelluar pathway for Mg 2+ and Ca 2+ in claudin-based TJs [3,27]. A recent report by Hou et al [11] clearly demonstrated that claudin-16/ paracellin-1 modulated the ion selectivity of the TJ by selectively increasing the permeability of Na + with no effect on Cl -when transfected into LLC-PK1 epithelial cells, and suggested that a loss of claudin-16/paracellin-1 function in the TAL could lead to losing the lumen-positive potential as the driving force for the reabsorption of Mg 2+ .Claudin-16 is also responsible for renal tubular dysplasia with interstitial nephritis in Japanese black cattle [9,20]. This disease is inherited in an autosomal recessive mode and characterized by renal failure, growth retardation, and early death due to renal dysfunction with a high incidence.…”

“…Claudin-16 is also responsible for renal tubular dysplasia with interstitial nephritis in Japanese black cattle [9,20]. This disease is inherited in an autosomal recessive mode and characterized by renal failure, growth retardation, and early death due to renal dysfunction with a high incidence.…”

“…This disease is inherited in an autosomal recessive mode and characterized by renal failure, growth retardation, and early death due to renal dysfunction with a high incidence. Affected animals possess a 37-kb or 56-kb deletion in the CLDN16 gene [9,10], resulting in the total lack of claudin-16 protein. Kidneys from one-to two-month-old calves affected revealed the presence of immature renal tubules without lumina accompanied by moderate interstitial fibrosis, whereas the numbers and distribution of the glomeruli appeared to be nearly normal.…”

Carrier Rate of Factor XI Deficiency in Stunted Japanese Black Cattle

“…CL-16 deficiency was examined using the DNA-based tests developed by Hirano et al [4]. Renal dysplasia was diagnosed from pathological findings.…”