{'fraction_non_alphanumeric': 0.03287108371854135, 'fraction_numerical': 0.009244992295839754, 'mean_word_length': 5.471760797342193, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Effect of Renal Tubule-Specific Knockdown of the Na+/H+ Exchanger NHE3 in Akita Diabetic Mice.

NHE3 contributes to Na+/bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knock-down (Pax8-Cre; NHE3-KO) were generated. NHE3-KO had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate and glucose (phosphoenolpyruvate carboxykinase-PEPCK) in proximal tubules and proton and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in non-diabetic and diabetic NHE3-KO versus wild-type mice, but was associated with renal upregulation of pro-inflammatory markers. Higher renal PEPCK expression in NHE3-KO was associated with lower SGLT2 and higher SGLT1 expression, indicating a downward tubular shift in sodium and glucose reabsorption. NHE3-KO was associated with lesser kidney weight (KW) and GFR independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing KW and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type; stronger SGLT1 engagement could have affected KW and GFR responses. Chronic kidney disease (CKD) in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids (BCAA) and Krebs cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in non-diabetic NHE3-KO, possibly reflecting BCAA use for ammoniagenesis and Krebs cycle upregulation to support formation of ammonia, bicarbonate and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.