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Hypertension-Mediated Albuminuria Is Associated with Reduced Lysosomal Activity in the Kidney and the Heart

Background: Recent studies suggest that expression of the transforming growth factor-β (TGF-β)-inducible gene-h3 (βig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension. Methods: We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson’s trichrome stain. Renal and cardiac TGF-β1 and βig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity. Results: SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal βig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-β1 and βig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment. Conclusions: These findings implicate for the first time βig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.